[go: up one dir, main page]
Skip to main content
Download PDF

Intricate effects of post-translational modifications in liver cancer: mechanisms to clinical applications

Journal of Translational Medicine volume 22, Article number: 651 (2024) Cite this article

Abstract

Liver cancer is a significant global health challenge, with hepatocellular carcinoma (HCC) being the most prevalent form, characterized by high incidence and mortality rates. Despite advances in targeted therapies and immunotherapies, the prognosis for advanced liver cancer remains poor. This underscores the urgent need for a deeper understanding of the molecular mechanisms underlying HCC to enable early detection and the development of novel therapeutic strategies. Post-translational modifications (PTMs) are crucial regulatory mechanisms in cellular biology, affecting protein functionality, interactions, and localization. These modifications, including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation, occur after protein synthesis and play vital roles in various cellular processes. Recent advances in proteomics and molecular biology have highlighted the complex networks of PTMs, emphasizing their critical role in maintaining cellular homeostasis and disease pathogenesis. Dysregulation of PTMs has been associated with several malignant cellular processes in HCC, such as altered cell proliferation, migration, immune evasion, and metabolic reprogramming, contributing to tumor growth and metastasis. This review aims to provide a comprehensive understanding of the pathological mechanisms and clinical implications of various PTMs in liver cancer. By exploring the multifaceted interactions of PTMs and their impact on liver cancer progression, we highlight the potential of PTMs as biomarkers and therapeutic targets. The significance of this review lies in its potential to inform the development of novel therapeutic approaches and improve prognostic tools for early intervention in the fight against liver cancer.

Introduction

Liver cancer is the sixth most prevalent cancer (4.3% of all cancer sites) and the third leading cause of cancer-related mortality (7.8% of all cancer sites) worldwide, according to Global Cancer Statistics 2022 [1,2,3]. Hepatocellular carcinoma (HCC) accounts for 75–85% of liver cancer cases. The incidence of liver cancer shows notable geographical variations, with East Asia and Sub-Saharan Africa experiencing the highest rates, largely due to the varying prevalence of risk factors such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, aflatoxin exposure, chronic alcohol use, and non-alcoholic fatty liver disease (NAFLD) [4,5,6,7]. Recent strides in molecular biology have shed light on the complex interplay of genetic, epigenetic, and environmental factors in liver cancer pathogenesis [8,9,10,11]. The classification of HCC into molecular subtypes based on genetic variations has introduced precision medicine, enabling treatment customization according to the unique genetic features of individual patients [12,13,14,15]. The emergence of immunotherapy, particularly checkpoint inhibitors like nivolumab and pembrolizumab, has marked a new era in HCC treatment, offering hope for better outcomes [12, 16,17,18,19]. However, challenges such as tumor heterogeneity, late-stage diagnosis, and resistance to systemic therapies persist, contributing to an overall five-year survival rate of less than 20% for patients with liver cancer [9, 20, 21]. These challenges underscore the urgent need for innovative diagnostic tools and therapeutic strategies, emphasizing the critical role of ongoing research in unraveling the mechanisms of liver cancer.

Post-translational modifications (PTMs), the covalent addition of specific chemical groups to proteins after translation, represent a sophisticated mechanism for controlling protein function, localization, and interactions [22,23,24,25]. These modifications, which include phosphorylation, acetylation, ubiquitination, methylation, and glycosylation, dynamically alter protein activities, enabling cells to precisely respond to various stimuli [24, 26,27,28]. Among these, phosphorylation, which is critical for cellular processes, is the most extensively studied PTM [29,30,31,32,33]. The balance between kinases and phosphatases is vital for maintaining cellular signaling integrity. Meanwhile, acetylation affects gene expression by modifying chromatin accessibility, influencing several biological processes [34,35,36,37]. Methylation predominantly occurs within the cell nucleus and on nuclear proteins, where lysine and arginine residues are the principal targets [38,39,40]. Glycosylation involves the enzymatic attachment of sugar moieties to serine and/or threonine residues on proteins. It encompasses three prevalent forms: N-glycosylation, O-glycosylation, and glypiation [41,42,43,44,45]. Advancements in proteomics have deepened the understanding of PTMs, revealing their extensive involvement in both physiological processes and disease progression, including cancer [46,47,48]. Emerging research has highlighted that PTMs contribute to HCC tumorigenesis and cancer progression by influencing cellular proliferation, apoptosis, invasion, deoxyribonucleic acid (DNA) repair, autophagy, metabolism, chemotherapy resistance, and immune evasion (Fig. 1) [49,50,51,52]. For example, dysregulation of phosphorylation controls critical signaling pathways involved in cell growth and apoptosis [53, 54]. Acetylation affects chromatin structure and gene expression, whereas ubiquitination regulates protein degradation, influencing cell cycle progression and DNA damage response [37, 55]. Methylation has emerged as a key player in modulating the complex interplay between genetic and environmental factors that drive tumor initiation, progression, and resistance to therapies [38, 56, 57]. Glycosylation affects cell-to-cell and cell-to-matrix interactions, crucial for tumor metastasis (Table 1) [58,59,60]. Inhibiting specific enzymes responsible for the addition or removal of PTMs has unveiled the complex interplay between PTMs and liver cancer and revealed promising avenues for advancements in the diagnosis, prognostic prediction, and targeted therapies of liver cancer [48, 61].

Fig. 1
figure 1

Landscape of post-translational modifications in liver cancer. Various post-translational modifications (PTMs) are instrumental in the progression of liver cancer, modulating the function and activity of target molecules involved in a range of malignant biological processes. These processes encompass but are not limited to cell proliferation, migration and invasion, autophagy, metabolic reprogramming, chemoresistance, and immune evasion. The diverse regulatory mechanisms of PTMs in liver cancer highlight their critical roles in tumor progression. Insights into the epigenetic landscape obtained by exploring PTMs in liver cancer have significant implications for developing targeted therapies, prognostic assessment, drug efficacy prediction, and early clinical diagnosis

Full size image
Table 1 Effects and regulatory mechanisms of post-translational modifications in the carcinogenesis of liver cancer
Full size table

This review aims to highlight the critical role of PTMs in the pathogenesis and progression of liver cancer, emphasizing the most extensively explored PTMs, mainly including phosphorylation, acetylation, methylation, and glycosylation. By dissecting the intricate mechanisms through which PTMs influence key cellular processes in liver cancer, the paper seeks to elucidate their potential as therapeutic targets, discuss the challenges in targeting these modifications, and explore promising research directions (Table 2). Ultimately, this review aims to improve diagnostic accuracy, prognostic prediction, and the personalization of treatment strategies for liver cancer by leveraging the insights gained from the study of PTMs in HCC pathogenesis.

Table 2 Clinical significance of post-translational modifications in liver cancer
Full size table

Literature search strategy

To identify relevant and high-quality literature, we performed an extensive search across databases including PubMed, Scopus, and Web of Science. Our search was confined to articles published from January 2017 to April 2024. We used keywords such as “liver cancer,” “hepatocellular carcinoma,” “post-translational modifications,” “phosphorylation,” “acetylation,” “methylation,” “ubiquitination,” and “glycosylation.” We selected articles based on their pertinence to PTMs in HCC, emphasizing those that offer insights into molecular mechanisms, diagnostic implications, and therapeutic potential. After conducting the keyword searches, we focused on reviewing high-impact and high-quality articles. We prioritized studies that were most relevant to our research, ensuring a comprehensive coverage of the role of PTMs in liver cancer. This thorough screening process allowed us to incorporate the most pertinent findings and provide a detailed understanding of the role of PTMs in liver cancer.

Expression and role of PTMs in liver cancer

Phosphorylation and its implications in liver cancer

Increasing research has revealed a significant correlation between PTMs and the clinicopathological features and prognosis of patients with liver cancer [61,62,63,64]. Phosphorylation, as a pivotal PTM, is reported to have a strong association with tumor pathological grading and poor prognosis in liver cancer [65,66,67,68,69]. Among the proteins studied, creatine kinase B (CKB) shows markedly higher expression in HCC cell lines Huh7, liver cancer metastasis 3 (HCCLM3) compared to normal liver cells, suggesting its oncogenic potential [68]. Analysis of The Cancer Genome Atlas (TCGA) database and immunohistochemistry (IHC) staining of HCC samples confirmed CKB’s upregulation in tumors, correlating high CKB phosphorylation with poorer patient survival outcomes. After pathological grading of human HCC samples based on intrahepatic metastasis levels, it was observed that LOXL3 phosphorylation at S704 was markedly elevated in high-grade tissues [69]. Furthermore, increased levels of pLOXL3-Ser704 were associated with a poorer prognosis and greater resistance to chemotherapy in HCC patients. Moreover, increased phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1) correlates with reduced survival rates of patients with HCC, positioning PCK1 phosphorylation as a potential prognostic marker for HCC outcomes [70].

Mechanistically, recent studies have highlighted the critical role of abnormal protein phosphorylation in HCC progression, influencing cell proliferation, metabolism, immune evasion, and chemotherapy resistance [68,69,70,71]. For example, insulin-like growth factor 1 receptor (IGF1R) activation leads to protein kinase B (AKT)-mediated CKB T133 phosphorylation and glutathione peroxidase 4 (GPX4) S104 phosphorylation, enhancing cell survival by inhibiting ferroptosis and lipid peroxidation. This process underscores the importance of the AKT/CKB/GPX4 axis in developing resistance to oxidative stress in HCC [68]. Additionally, research has revealed that oxaliplatin resistance in HCC involves the phosphorylation of lysyl oxidase-like 3 (LOXL3). LOXL3, upon activation by epidermal growth factor (EGF) and its receptor (EGFR) signaling, contributes to its translocation into mitochondria through the mitochondrial import receptor translocase of outer mitochondrial membrane 20 (TOM20). The mitochondrial kinase adenylate kinase 2 (AK2) phosphorylates LOXL3 at S704, which stabilizes dihydroorotate dehydrogenase (DHODH) and enables HCC cells to resist oxaliplatin-induced ferroptosis [69]. Combining oxaliplatin with inhibitors targeting the LOXL3-DHODH axis effectively suppressed tumor growth in mouse models with advanced HCC with the LOXL3-S704D mutant, highlighting a novel resistance mechanism and therapeutic strategy. Metformin’s anti-tumor effects on various cancer types have revealed the role of dedicator of cytokinesis protein 1 (DOCK1), a canonical guanine nucleotide exchange factor (GEF) for Ras-related C3 botulinum toxin substrate (RAC) family small guanosine triphosphatases (GTPases), in influencing metformin’s efficacy in HCC [71]. Metformin-induced phosphorylation of DOCK1 at Y722 and Y1811 increases the level of RAC1-GTP to activate RAC1 in HCC PLC, SNU-449, and Hep3B cells, contributing to increased cell survival and resistance to metformin. However, combining metformin with the DOCK1 inhibitor (TBOPP) significantly reduces HCC cell viability, suggesting a synergistic approach to enhancing metformin’s anti-cancer effects. Furthermore, the combination of metformin and TBOPP has exhibited a dramatically synergistic inhibition on cell viability in both in vivo PLC, SNU449, and Hep3B cells and patient-derived HCC organoids. This introduces a promising therapeutic strategy of integrating metformin with targeted inhibition of specific signaling pathways, such as the DOCK1-mediated activation of RAC1, to potentiate the antitumor effects of metformin in liver cancer. Recent insights also connect phosphorylation with macrophage M2 polarization and anti-programmed cell death 1 (anti-PD1) resistance [72]. The studies have discovered the upregulation of zinc finger protein 64 (ZFP64) in tumor tissues of patients with HCC resistance to anti-PD1 therapy. Protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, facilitating its nuclear translocation and transcription activation of colony-stimulating factor 1 (CSF1). CSF1 promotes the recruitment and polarization of M2 macrophage, fostering an immunosuppressive tumor microenvironment (TME). The application of protein kinase inhibitors such as Gö6976 and lenvatinib has been shown to reset TME to favor immune-mediated tumor suppression and restore cell sensitivity to anti-PD1 therapy [15]. In Huh7 and Hep3B HCC cells, AKT prompts PCK1 phosphorylation at S90 to translocate to the endoplasmic reticulum (ER), where it respectively phosphorylates ER anchor proteins INSIG1/2 at S207 and S151. This phosphorylation diminishes sterol binding of INSIG1/2, leading to sterol regulatory element-binding proteins (SREBPs) activation and subsequent enhanced lipogenesis and tumor growth [70]. These findings not only elucidate the multifaceted role of phosphorylation in HCC but also offer potential targets for prognosis prediction and therapeutic intervention, emphasizing the need for integrated strategies to tackle HCC’s complexity (Fig. 2).

Fig. 2
figure 2

Intricate mechanisms of several common post-translational modifications in liver cancer. Phosphorylation, acetylation, ubiquitination, methylation, and glycosylation are prominently explored PTMs that significantly influence a wide array of molecular mechanisms, playing pivotal roles in the initiation and progression of liver cancer. These modifications alter protein function, stability, localization, and interactions, thereby modulating key signaling pathways and cellular processes. In liver cancer, phosphorylation activates oncogenic molecules such as GPX4, LOX3, DOCK1, INSIG1/2, and ZFP64, thereby promoting cell proliferation, survival, lipogenesis, immune escape, and resistance to oxaliplatin, metformin, and immunotherapy. Acetylation participates in modifying genes involved in cell glycolysis, proliferation, glutaminolysis, invasion, stem cell-like characteristics, and immune evasion in liver cancer. Arginine methylation, mediated by diverse PRMTs, influences various molecular pathways and cellular processes critical in cancer development, including cell proliferation, ferroptosis, serine synthesis, glycolysis, cell migration, invasion, and resistance to oxaliplatin. Alterations in glycosylation patterns modulate the activity and localization of cell surface receptors and adhesion molecules, thereby contributing to various cellular processes, including glycolysis, cell proliferation, cell invasion, adhesion, and metastasis. The intricate relationship between post-translational modifications and liver cancer progression highlights its potential as a target for therapeutic intervention

Full size image

Acetylation and its implications in liver cancer

In recent years, advancements in precision medicine have revealed abnormal acetylation levels in liver cancer, underscoring its potential prognostic value by correlating with clinicopathological factors [73,74,75,76,77]. For example, elevated levels of Sirtuin 2 (SIRT2) in HCC, as opposed to adjacent normal tissues, are associated with more aggressive disease features and poor prognosis, such as advanced tumor stage and larger size, highlighting their roles in HCC progression [78]. Moreover, alterations in the expression of phosphoglycerate kinase 1 (PGK1) and its acetylation by p300/CBP-associated factor (PCAF) are significantly upregulated in HCC tissues. This overexpression correlates with decreased survival rates and increased recurrence risk, underscoring its oncogenic role in liver cancer [79]. Research also shows that lower expression of the mitochondrial protein general control of amino acid synthesis 5 like 1 (GCN5L1) in HCC tissues correlates with increased glutaminase (GLS1/GLS2) acetylation and poorer patient survival, highlighting GCN5L1 as a potential prognostic indicator [80]. A significant upregulation in both the expression and acetylation of the stimulatory G protein alpha subunit (GαS protein) has been documented in dysplastic nodules and HCC tissues. Elevated levels of GαS protein are indicative of advanced tumor stages and poorer histological differentiation, inversely affecting both overall and disease-free survival outcomes. Cox proportional hazards regression analysis identifies high GαS levels as an independent prognostic factor for adverse outcomes in patients with HCC [81].

In the context of liver cancer, altered acetylation profiles have been found to influence cancer cell metabolism and the tumor microenvironment, offering insights into the metabolic vulnerabilities of liver cancer cells [74, 77, 82, 83]. It has been acknowledged that lymphocyte-activation gene 3 (LAG-3), a transmembrane protein on activated T cells, inhibits antigen-specific T cell activation by interacting with fibroblast growth factor-inducible 14 (FGL1). Research across various HCC cell lines has shown that SIRT2 enhances immune evasion by deacetylating FGL1, thus increasing its protein stability [78]. Further research demonstrates that inhibiting SIRT2 with AGK2, in conjunction with programmed death-ligand 1 (PD-L1) blockade, enhances FGL1 acetylation, restoring tumor-infiltrating cluster of differentiation 8 (CD8 +) T cell populations, suppressing tumor growth, and boosting survival in mouse models. Remarkably, aspirin has been shown to amplify the effects of PD-L1 blockade in HCC Hepa 1–6 and H22 tumor models by directly acetylating FGL1, facilitating its degradation and offering a potential strategy to enhance HCC immunotherapy [78, 84]. The increased acetylation of PGK1 at K323 has been identified as a critical oncogenic mechanism, enhancing its role in cancer progression. Importantly, the depletion of PGK1 markedly reduces cancer glycolysis, cell proliferation, and tumorigenesis of HCC in mouse xenograft models [79]. This evidence points to the potential of targeting PGK1 and its post-translational modifications as a novel therapeutic approach in liver cancer treatment. Additionally, glutamine addiction is a key metabolic pathway promoting cancer cell proliferation in HCC. In HCC models induced by the combination of diethylnitrosamine (DEN) and carbon tetrachloride (CCL4), mitochondrial GCN5L1 inhibits tumor growth by reducing GLS1/2 acetylation and activity, highlighting its role in regulating glutamine addiction during HCC progression. The loss of GCN5L1 enhances glutaminolysis and activates the mechanistic target of rapamycin C1 (mTORC1) pathway, fueling cell proliferation and tumor development [80]. Targeting GCN5L1 to disrupt HCC’s metabolic reliance on glutamine offers a promising therapeutic strategy by exploiting metabolic vulnerabilities in liver cancer. Increasing studies underscore the involvement of cancer stem cells (CSCs) in multiple malignant processes during HCC development, including tumor initiation, relapse, metastasis, and drug resistance [85,86,87,88]. Recent studies have highlighted the pivotal role of scavenger receptor class B member 2 (SCARB2) in maintaining the stem-like characteristics of HCC cells. The interaction between SCARB2 and MYC facilitates the acetylation of MYC and enhances its transcriptional activity, leading to increased proliferation of HCC cells, the formation of colonies, and the preservation of cancer stem cell-like properties. Deleting SCARB2 significantly hampers tumor growth and metastasis, driven by oncogenic MYC activation. Intervening in the SCARB2-MYC pathway through brefeldin A administration showcases a potent targeted therapy for liver cancer by targeting stem cell-like properties [89]. Furthermore, acetylation modifications have also been linked to the malignant transformation of hepatocellular carcinoma progenitor cells (hcPCs) into established HCC. Elevated levels of GαS protein in dysplastic nodules and HCC tissues, demonstrating a clear association with enhanced STAT3 phosphorylation [81]. The elevation of GαS in liver cancer tissues underscores its critical function in HCC progression and prognosis, providing valuable insights for preventing hepatocarcinogenesis.

Methylation and its implications in liver cancer

Emerging evidence indicates the crucial role of abnormal methylation patterns in the progression of liver cancer. The overexpression of protein arginine methyltransferases (PRMTs), which leads to abnormal methylation, is frequently associated with a poor prognosis in liver cancer [90, 91]. Recently, PRMT3 expression has been found to be significantly elevated in HCC, and this high expression is linked to poor clinical outcomes [92]. Moreover, elevated PRMT3 expression at both messenger ribonucleic acid (mRNA) and protein levels in oxaliplatin-resistant PLC-8024-R and Huh7-R cell lines pinpoints its pivotal role in oxaliplatin resistance. This positions PRMT3 overexpression as a potential biomarker for identifying oxaliplatin resistance in patients with liver cancer, linking higher PRMT3 levels to poorer outcomes and diminished therapeutic responses to oxaliplatin-based hepatic artery infusion chemotherapy (HAIC) [93]. Notably, elevated PRMT1 levels in HCC are linked to larger tumor size, increased microvascular invasion, elevated tumor, node, metastasis (TNM) stages, and poorer survival outcomes, positioning them as potential prognostic indicators [94]. As a key enzyme in serine biosynthesis, an increase in methylation levels of PHGDH and its enhanced enzyme activity in HCC tissues correlates with poor patient outcomes [95]. In addition, the significantly higher arginine methylation of heat shock protein A8 (HSPA8) in tumor tissues correlate with diminished overall survival rates among patients, underscoring their potential as prognostic indicators for liver cancer [96].

Emerging research has highlighted that methylation modifications orchestrate a wide array of cellular processes, contributing to the development and progression of HCC [91, 97,98,99]. Methylation processes play a pivotal role in the oncogenesis of HBV-induced HCC, specifically through the modulation of the hepatitis B virus X (HBx) protein [100,101,102,103,104]. Recent studies have illuminated the critical involvement of arginine methylation in regulating HBx-induced ferroptosis, a crucial process in cancer progression [102, 105,106,107]. HBx is found to elevate the expression of PRMT9 in HCC HepG2 and Huh7 cells, leading to increased arginine methylation of HSPA8. This modification significantly upregulates CD44 expression, contributing to the suppression of ferroptosis and fostering tumor growth and cell proliferation. This intricate understanding of HBx-induced HCC highlights the therapeutic potential of targeting arginine methylation pathways in HBV-related liver cancer management [96]. Recent research has highlighted that methylation also plays a significant role in regulating the resistance of liver cancer cells to conventional therapies [108]. PRMT3 mediates the methylation of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which in turn stabilizes the mRNA of heart development protein with EGF-like domains 1 (HEG1) in an m6A-dependent manner [93]. This process promotes the proliferation and survival of liver cancer cells, contributing to oxaliplatin resistance, confirmed through in vitro and in vivo experiments. These insights shed light on the intricate role of methylation in the adaptive mechanisms of liver cancer to chemotherapy, potentially guiding the stratification of patients for oxaliplatin-based HAIC therapy and the development of targeted interventions to overcome drug resistance. The association between methylation and metabolic deregulation has been found to affect the pathogenesis of HCC. The enzyme PRMT1 is identified as the mediator of phosphoglycerate dehydrogenase (PHGDH) methylation, which in turn elevates its catalytic efficiency. As a key enzyme in serine biosynthesis, an increase in methylation levels of PHGDH and its enhanced enzyme activity in HCC tissues correlates with poor patient outcomes. This augmentation of PHGDH activity boosts serine production, mitigates oxidative stress, and eventually promotes HCC cell proliferation and tumor growth. Notably, in the HCC patient-derived xenograft (PDX) and subcutaneous HCC cell-derived xenograft models, the use of a trans-activator of transcription (TAT)-tagged non-methylatable peptide to block PHGDH methylation effectively inhibits serine synthesis and suppresses HCC growth [95]. This finding highlights the potential of targeting PHGDH methylation as a novel therapeutic intervention for liver cancer by disrupting critical metabolic dependencies involved in tumor growth and survival. Moreover, recent research has highlighted the intricate interplay between methylation modifications and ubiquitination processes, revealing their combined impact on accelerating HCC progression [109]. PRMT5, by methylating the tumor suppressor retinoic acid receptor-related orphan receptor α (RORα), enhances its interaction with the E3 ubiquitin ligase itchy E3 ubiquitin protein ligase (ITCH). This interaction promotes the ubiquitination and subsequent degradation of RORα. Interestingly, this process is mitigated by oxidative stress-induced reactive oxygen species (ROS), which reduce PRMT5 protein levels, thereby restoring RORα expression. Elevated ROS levels, under specific oxidative stress conditions, are shown to inhibit the proliferation, migration, and invasion of HCC HepG2 cells [110]. Thymidine kinase 1 (TK1) has also been implicated in the metabolic reprogramming associated with HCC progression, orchestrating the complex interplay between methylation and ubiquitination. TK1 interacts with PRMT1, stabilizing it by inhibiting ubiquitination and subsequent degradation mediated by tripartite motif containing 48 (TRIM48). Increased PRMT1 levels drive the methylation of phosphofructokinase/fructose bisphosphatase type-3 (PFKFB3), leading to enhanced glycolysis, proliferation, migration, and invasion of tumor cells [94]. The involvement of methylation in altering cellular metabolism presents promising therapeutic opportunities, underscoring the potential to target methylation as a strategy for metabolic reprogramming in HCC treatment (Fig. 3).

Fig. 3
figure 3

Clinical significance of multiple post-translational modifications in liver cancer management. The aberrant expression of PTMs, including phosphorylation, acetylation, methylation, and glycosylation, is linked to unfavorable clinical pathologies and prognosis in liver cancer, underlining their significance as prognostic biomarkers. Additionally, these PTMs have been identified as markers of resistance to chemotherapy, highlighting their utility in guiding treatment strategies. Given the complex involvement of PTMs in the pathogenesis of liver cancer, interventions targeting these modifications have demonstrated promising results in impeding tumor proliferation across various preclinical models. This insight reinforces the value of PTMs as potential therapeutic targets, paving the way for more effective liver cancer treatments

Full size image

Glycosylation and its implications in liver cancer

Glycosylation profoundly influences HCC progression by altering a wide array of pro-tumorigenic molecules and signaling pathways across the disease’s various stages [59, 111]. It has also demonstrated that beta-1,3-galactosyltransferase 5 (B3GALT5) is overexpressed in HCC, correlating with poor prognostic outcomes [112]. Moreover, the upregulation of soluble carrier family 35 member A2 (SLC35A2) in HCC tissues, particularly those with lymph node infiltration or metastasis, underscores the enhancement of HCC’s metastatic potential [113]. The initiation of O-glycosylation by polypeptide N-acetylgalactosaminyltransferases (GALNTs) has been observed to reduce median survival in a mouse liver cancer model [114].

A key modulation involves the crosstalk between O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, adenosine diphosphate (ADP)-ribosylation, and ubiquitination, crucially enhancing the DNA damage response during HCC progression. Enhanced O-GlcNAcylation of ADP-ribose glycohydrolase (PARG) mitigates the autoubiquitination of DNA damage-binding protein 1 (DDB1), thus stabilizing DDB1. The stabilization of DDB1 is critical for the targeted degradation of the oncogene cellular myelocytomatosis oncogene c-Myc in HCC Huh7 cells, thereby effectively impeding HCC tumorigenesis [115]. Concurrently, the impact of glycosylation extends beyond DNA repair to the metabolic landscape of HCC. Enhanced B3GALT5 activity facilitates the glycosylation of mTOR, activating its downstream effector, p70 ribosomal protein S6 kinase (p70s6k) [112]. This activation propels glycolysis, fostering cell proliferation and contributing to the development of HCC. This mechanistic understanding accentuates the pivotal role of glycosylation in manipulating cellular metabolism, driving the aggressive behavior of liver cancer cells [116, 117]. Consequently, targeting the glycosylation-mediated activation of the mTOR/p70s6k pathway presents a promising avenue for therapeutic intervention in HCC. The importance of glycosylation in HCC metastasis further exemplifies its role in cancer progression. Recent research underscores the critical influence of glycosylation modifications on the invasive phenotype associated with intrahepatic metastasis in liver cancer. Studies show increased activity of GALNTs, relocating from the Golgi apparatus to the endoplasmic reticulum (ER). This relocation facilitates the glycosylation of matrix metalloproteinase 14 (MMP14) by ER-targeted GALNT1 (ER-G1), markedly enhancing matrix degradation and tissue invasion, thereby promoting metastasis [114]. The altered expression of SLC35A2 recruits β-1,4-galactosyltransferase (B4GalT1) to the Golgi apparatus in HCC cells. The interaction between SLC35A2 and B4GalT1 in the Golgi apparatus drives the invasive capabilities of HCC cells, emphasizing the therapeutic potential of targeting these glycosylation pathways [113]. Additionally, β-galactoside α2,6 sialyltransferase 1(ST6GAL1) has been considered as a suppressor in HCC metastasis. By modulating the sialylation of melanoma cell adhesion molecule (MCAM), ST6GAL1 inhibits the migration and invasion of HCC cells, showcasing novel avenues through which glycosylation can influence cancer progression [118]. Collectively, these insights highlight the multifaceted role of glycosylation in HCC progression, from metabolic reprogramming to invasion and metastasis. Targeting glycosylation offers a promising therapeutic strategy to disrupt the molecular interplay driving HCC progression.

Given the significance of PTMs in liver cancer, our review highlights their potential as promising prognostic markers in liver cancer. We also elaborate on the regulatory mechanisms of PTMs in liver cancer pathogenesis, emphasizing the applications of PTMs as innovative alternatives to existing therapeutic strategies for liver cancer. Targeting specific PTMs precisely modulates cancer-related pathways and achieves promising results in diverse preclinical trials, suggest that further validation in large clinical cohorts is essential. Future clinical studies should evaluate the efficacy of these therapies across diverse patient populations, assess long-term safety and side effects. Comparative studies with existing treatments will help determine their overall therapeutic value, while biomarker development will aid in personalizing treatment plans. Moreover, incorporating green nanomaterials into PTM-targeted therapies presents a sustainable and effective approach to liver cancer treatment. Green nanomaterials, synthesized through eco-friendly processes, offer significant advantages with the minimized use of toxic solvents and enhanced biocompatibility in biomedical applications, including liver cancer therapy [119,120,121,122,123,124]. Advanced HCC often exhibits strong resistance to chemotherapy, with traditional drugs failing to achieve satisfactory therapeutic efficacy. Recent advances in nanotechnology, bioengineering, and chemical biology have led to new approaches to improve the efficacy and safety of liver cancer treatments [125,126,127,128,129]. In recent years, various nanoparticles and nanoparticle drug delivery systems have been extensively explored to enhance the therapeutic efficacy of the oral kinase inhibitor sorafenib in HCC [130]. Combining PTM-targeted modifications with nanomaterials represents a meaningful direction for future liver cancer therapies. This strategy holds promise for improving treatment outcomes and providing more effective therapeutic options for patients with liver cancer.

Conclusion

The worse survival rates for advanced liver cancer underscore the critical need for a deeper understanding of the disease’s molecular underpinnings to bolster early detection and develop innovative treatment strategies. An in-depth investigation of epigenetic alterations in HCC progression has revealed the pivotal roles of various PTMs in maintaining normal physiological activities and their contribution to the pathogenesis and progression of diseases. Several studies identify PTMs as key drivers in the malignant progression of liver cancer, with a wide range of aberrant PTMs observable at different stages of the disease. These biochemical alterations, including phosphorylation, acetylation, methylation, and glycosylation, modify proteins at the post-translational level, impacting their functionality and downstream cancer-related signaling pathways. Therefore, abnormalities in multiple PTMs contribute to an array of malignant cellular activities, such as cell proliferation, migration, autophagy, chemoresistance, immune evasion, and various metabolic reprogramming. Furthermore, as studies delve deeper into the mechanisms of PTMs in the pathogenesis of liver cancer, targeted biomarkers and therapeutic approaches focusing on PTMs have shown promising clinical outcomes in preclinical experiments. Although various PTMs and their impacts on HCC pathogenic processes have been studied, there exist challenges in translating basic research insights on PTMs in liver cancer into clinical practice. The dynamic properties of PTMs and their context-dependent effects complicate delineating their precise contributions to the pathogenesis and progression of HCC. Most importantly, the ubiquity of PTMs in normal physiological processes and potential off-target effects significantly increase the difficulty in developing drugs targeting specific PTMs.

In summary, PTMs play a prominent role in driving the development and progression of liver cancer. Mounting evidence has revealed that dysregulated PTMs are implicated in the regulation of multiple biological processes by affecting the post-transcriptional modification of the associated genes. This promises PTMs to be more precise and effective therapeutic targets and prognostic markers to help improve the prognosis of liver cancer. Continued exploration of the molecular mechanisms into the intricacies of PTMs with HCC carcinogenesis is vital for unlocking new avenues for the treatment of liver cancer.

Availability of data and materials

Not applicable.

Abbreviations

HCC:

Hepatocellular carcinoma

PTMs:

Post-translational modifications

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

NAFLD:

Non-alcoholic fatty liver disease

CKB:

Creatine kinase B

TCGA:

The Cancer Genome Atlas

IHC:

Immunohistochemistry

IGF1R:

Insulin-like growth factor 1 receptor

GPX4:

Glutathione peroxidase 4

LOXL3:

Lysyl oxidase-like 3

EGF:

Epidermal growth factor

DHODH:

Dihydroorotate dehydrogenase

anti-PD1:

Anti-programmed cell death 1

ZFP64:

Zinc finger protein 64

PKCα:

Protein Kinase C alpha

CSF1:

Colony stimulating factor 1

TME:

Tumor microenvironment

PCK1:

Phosphoenolpyruvate carboxykinase 1

HSPA8:

Heat shock protein A8

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63. https://doi.org/10.3322/caac.21834.

    Article  PubMed  Google Scholar 

  2. Wilson JF. Liver cancer on the rise. Ann Intern Med. 2005;142:1029–32. https://doi.org/10.7326/0003-4819-142-12_part_1-200506210-00024.

    Article  PubMed  Google Scholar 

  3. Peng J, Lü M, Peng Y, Tang X. Global incidence of primary liver cancer by etiology among children, adolescents, and young adults. J Hepatol. 2023;79:e92–4. https://doi.org/10.1016/j.jhep.2023.02.019.

    Article  PubMed  Google Scholar 

  4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  5. Kim BH, Park JW. Epidemiology of liver cancer in South Korea. Clin Mol Hepatol. 2018;24:1–9. https://doi.org/10.3350/cmh.2017.0112.

    Article  CAS  PubMed  Google Scholar 

  6. Chen JG, Zhang SW. Liver cancer epidemic in China: past, present and future. Semin Cancer Biol. 2011;21:59–69. https://doi.org/10.1016/j.semcancer.2010.11.002.

    Article  PubMed  Google Scholar 

  7. Duan XY, Zhang L, Fan JG, Qiao L. NAFLD leads to liver cancer: do we have sufficient evidence? Cancer Lett. 2014;345:230–4. https://doi.org/10.1016/j.canlet.2013.07.033.

    Article  CAS  PubMed  Google Scholar 

  8. Li G, Yao Q, Liu P, Zhang H, Liu Y, Li S, et al. Critical roles and clinical perspectives of RNA methylation in cancer. MedComm. 2020;2024(5): e559. https://doi.org/10.1002/mco2.559.

    Article  CAS  Google Scholar 

  9. Huang PS, Wang LY, Wang YW, Tsai MM, Lin TK, Liao CJ, et al. Evaluation and application of drug resistance by biomarkers in the clinical treatment of liver cancer. Cells. 2023. https://doi.org/10.3390/cells12060869.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nikolaou K, Sarris M, Talianidis I. Molecular pathways: the complex roles of inflammation pathways in the development and treatment of liver cancer. Clin Cancer Res. 2013;19:2810–6. https://doi.org/10.1158/1078-0432.Ccr-12-1961.

    Article  CAS  PubMed  Google Scholar 

  11. He Y, Shi M, Wu X, Ma J, Ng KT, Xia Q, et al. Mutational signature analysis reveals widespread contribution of pyrrolizidine alkaloid exposure to human liver cancer. Hepatology. 2021;74:264–80. https://doi.org/10.1002/hep.31723.

    Article  CAS  PubMed  Google Scholar 

  12. Bruix J, Han KH, Gores G, Llovet JM, Mazzaferro V. Liver cancer: approaching a personalized care. J Hepatol. 2015;62:S144–56. https://doi.org/10.1016/j.jhep.2015.02.007.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Fu X, Zhang Y, Luo Q, Ju Y, Song G. Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer. Cancer Biol Med. 2023;20:816–29. https://doi.org/10.20892/j.issn.2095-3941.2023.0229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther. 2023;8:204. https://doi.org/10.1038/s41392-023-01468-7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hao L, Li S, Deng J, Li N, Yu F, Jiang Z, et al. The current status and future of PD-L1 in liver cancer. Front Immunol. 2023;14:1323581. https://doi.org/10.3389/fimmu.2023.1323581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zheng Y, Wang S, Cai J, Ke A, Fan J. The progress of immune checkpoint therapy in primary liver cancer. Biochim Biophys Acta Rev Cancer. 2021;1876: 188638. https://doi.org/10.1016/j.bbcan.2021.188638.

    Article  CAS  PubMed  Google Scholar 

  17. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer. 2020;1873: 188314. https://doi.org/10.1016/j.bbcan.2019.188314.

    Article  CAS  PubMed  Google Scholar 

  18. Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021;21:541–57. https://doi.org/10.1038/s41568-021-00383-9.

    Article  CAS  PubMed  Google Scholar 

  19. de Lope CR, Tremosini S, Forner A, Reig M, Bruix J. Management of HCC. J Hepatol. 2012;56(Suppl 1):S75-87. https://doi.org/10.1016/s0168-8278(12)60009-9.

    Article  PubMed  Google Scholar 

  20. Li L, Wang H. Heterogeneity of liver cancer and personalized therapy. Cancer Lett. 2016;379:191–7. https://doi.org/10.1016/j.canlet.2015.07.018.

    Article  CAS  PubMed  Google Scholar 

  21. Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies for cancer prevention in liver. Nat Rev Cancer. 2003;3:321–9. https://doi.org/10.1038/nrc1076.

    Article  CAS  PubMed  Google Scholar 

  22. Macek B, Forchhammer K, Hardouin J, Weber-Ban E, Grangeasse C, Mijakovic I. Protein post-translational modifications in bacteria. Nat Rev Microbiol. 2019;17:651–64. https://doi.org/10.1038/s41579-019-0243-0.

    Article  CAS  PubMed  Google Scholar 

  23. Vu LD, Gevaert K, De Smet I. Protein language: post-translational modifications talking to each other. Trend Plant Sci. 2018;23:1068–80. https://doi.org/10.1016/j.tplants.2018.09.004.

    Article  CAS  Google Scholar 

  24. Bradley D. The evolution of post-translational modifications. Curr Opin Genet Dev. 2022;76: 101956. https://doi.org/10.1016/j.gde.2022.101956.

    Article  CAS  PubMed  Google Scholar 

  25. Shu F, Xiao H, Li QN, Ren XS, Liu ZG, Hu BW, et al. Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Signal Transduct Target Ther. 2023;8:32. https://doi.org/10.1038/s41392-022-01300-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee JM, Hammarén HM, Savitski MM, Baek SH. Control of protein stability by post-translational modifications. Nat Commun. 2023;14:201. https://doi.org/10.1038/s41467-023-35795-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. DeShields RW. Gnathological considerations of a controversial nature. Ohio Dent J. 1977;51:23–7.

    CAS  PubMed  Google Scholar 

  28. Tolsma TO, Hansen JC. Post-translational modifications and chromatin dynamics. Essays Biochem. 2019;63:89–96. https://doi.org/10.1042/ebc20180067.

    Article  CAS  PubMed  Google Scholar 

  29. Patwardhan P, Miller WT. Processive phosphorylation: mechanism and biological importance. Cell Signal. 2007;19:2218–26. https://doi.org/10.1016/j.cellsig.2007.06.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Galinier A, Deutscher J. Sophisticated regulation of transcriptional factors by the bacterial phosphoenolpyruvate: sugar phosphotransferase system. J Mol Biol. 2017;429:773–89. https://doi.org/10.1016/j.jmb.2017.02.006.

    Article  CAS  PubMed  Google Scholar 

  31. Huang B, Zhao Z, Zhao Y, Huang S. Protein arginine phosphorylation in organisms. Int J Biol Macromol. 2021;171:414–22. https://doi.org/10.1016/j.ijbiomac.2021.01.015.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou T, Wang M, Cheng A, Yang Q, Tian B, Wu Y, et al. Regulation of alphaherpesvirus protein via post-translational phosphorylation. Vet Res. 2022;53:93. https://doi.org/10.1186/s13567-022-01115-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Derouiche A, Cousin C, Mijakovic I. Protein phosphorylation from the perspective of systems biology. Curr Opin Biotechnol. 2012;23:585–90. https://doi.org/10.1016/j.copbio.2011.11.008.

    Article  CAS  PubMed  Google Scholar 

  34. Gil J, Ramírez-Torres A, Encarnación-Guevara S. Lysine acetylation and cancer: a proteomics perspective. J Proteom. 2017;150:297–309. https://doi.org/10.1016/j.jprot.2016.10.003.

    Article  CAS  Google Scholar 

  35. King CM, Glowinski IB. Acetylation, deacetylation and acyltransfer. Environ Health Perspect. 1983;49:43–50. https://doi.org/10.1289/ehp.834943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baeza J, Smallegan MJ, Denu JM. Mechanisms and dynamics of protein acetylation in mitochondria. Trend Biochem Sci. 2016;41:231–44. https://doi.org/10.1016/j.tibs.2015.12.006.

    Article  CAS  PubMed  Google Scholar 

  37. Kouzarides T. Acetylation: a regulatory modification to rival phosphorylation? Embo j. 2000;19:1176–9. https://doi.org/10.1093/emboj/19.6.1176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Polevoda B, Sherman F. Methylation of proteins involved in translation. Mol Microbiol. 2007;65:590–606. https://doi.org/10.1111/j.1365-2958.2007.05831.x.

    Article  CAS  PubMed  Google Scholar 

  39. Stallcup MR. Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene. 2001;20:3014–20. https://doi.org/10.1038/sj.onc.1204325.

    Article  CAS  PubMed  Google Scholar 

  40. Nicholson TB, Chen T, Richard S. The physiological and pathophysiological role of PRMT1-mediated protein arginine methylation. Pharmacol Res. 2009;60:466–74. https://doi.org/10.1016/j.phrs.2009.07.006.

    Article  CAS  PubMed  Google Scholar 

  41. Eichler J. Protein glycosylation. Curr Biol. 2019;29:R229–31. https://doi.org/10.1016/j.cub.2019.01.003.

    Article  CAS  PubMed  Google Scholar 

  42. Rudd PM, Dwek RA. Glycosylation: heterogeneity and the 3D structure of proteins. Crit Rev Biochem Mol Biol. 1997;32:1–100. https://doi.org/10.3109/10409239709085144.

    Article  CAS  PubMed  Google Scholar 

  43. Schjoldager KT, Narimatsu Y, Joshi HJ, Clausen H. Global view of human protein glycosylation pathways and functions. Nat Rev Mol Cell Biol. 2020;21:729–49. https://doi.org/10.1038/s41580-020-00294-x.

    Article  CAS  PubMed  Google Scholar 

  44. Xu M, Yang A, Xia J, Jiang J, Liu CF, Ye Z, et al. Protein glycosylation in urine as a biomarker of diseases. Transl Res. 2023;253:95–107. https://doi.org/10.1016/j.trsl.2022.08.001.

    Article  CAS  PubMed  Google Scholar 

  45. Costa J, Hayes C, Lisacek F. Protein glycosylation and glycoinformatics for novel biomarker discovery in neurodegenerative diseases. Ageing Res Rev. 2023;89: 101991. https://doi.org/10.1016/j.arr.2023.101991.

    Article  CAS  PubMed  Google Scholar 

  46. Xiang T, Zhao S, Wu Y, Li L, Fu P, Ma L. Novel post-translational modifications in the kidneys for human health and diseases. Life Sci. 2022;311: 121188. https://doi.org/10.1016/j.lfs.2022.121188.

    Article  CAS  PubMed  Google Scholar 

  47. Pienkowski T, Kowalczyk T, Cysewski D, Kretowski A, Ciborowski M. Glioma and post-translational modifications: a complex relationship. Biochim Biophys Acta Rev Cancer. 2023;1878: 189009. https://doi.org/10.1016/j.bbcan.2023.189009.

    Article  CAS  PubMed  Google Scholar 

  48. Hermann J, Schurgers L, Jankowski V. Identification and characterization of post-translational modifications: clinical implications. Mol Asps Med. 2022;86: 101066. https://doi.org/10.1016/j.mam.2022.101066.

    Article  CAS  Google Scholar 

  49. Jarrold J, Davies CC. PRMTs and arginine methylation: cancer’s best-kept secret? Trend Mol Med. 2019;25:993–1009. https://doi.org/10.1016/j.molmed.2019.05.007.

    Article  CAS  Google Scholar 

  50. Zhang J, Xun M, Li C, Chen Y. The O-GlcNAcylation and its promotion to hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer. 2022;1877: 188806. https://doi.org/10.1016/j.bbcan.2022.188806.

    Article  CAS  PubMed  Google Scholar 

  51. Hu M, Zhang R, Yang J, Zhao C, Liu W, Huang Y, et al. The role of N-glycosylation modification in the pathogenesis of liver cancer. Cell Death Dis. 2023;14:222. https://doi.org/10.1038/s41419-023-05733-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016;15:18. https://doi.org/10.1186/s12943-016-0502-x.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Liu X, Zhang Y, Wang Y, Yang M, Hong F, Yang S. Protein phosphorylation in cancer: role of nitric oxide signaling pathway. Biomolecules. 2021. https://doi.org/10.3390/biom11071009.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trend Biochem Sci. 2005;30:43–52. https://doi.org/10.1016/j.tibs.2004.11.009.

    Article  CAS  PubMed  Google Scholar 

  55. Ayyadevara S, Balasubramaniam M, Kakraba S, Alla R, Mehta JL, Shmookler Reis RJ. Aspirin-mediated acetylation protects against multiple neurodegenerative pathologies by impeding protein aggregation. Antioxid Redox Signal. 2017;27:1383–96. https://doi.org/10.1089/ars.2016.6978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hyun K, Jeon J, Park K, Kim J. Writing, erasing and reading histone lysine methylations. Exp Mol Med. 2017;49: e324. https://doi.org/10.1038/emm.2017.11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zheng K, Chen S, Ren Z, Wang Y. Protein arginine methylation in viral infection and antiviral immunity. Int J Biol Sci. 2023;19:5292–318. https://doi.org/10.7150/ijbs.89498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stowell SR, Ju T, Cummings RD. Protein glycosylation in cancer. Annu Rev Pathol. 2015;10:473–510. https://doi.org/10.1146/annurev-pathol-012414-040438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang Y, Chen H. Protein glycosylation alterations in hepatocellular carcinoma: function and clinical implications. Oncogene. 2023;42:1970–9. https://doi.org/10.1038/s41388-023-02702-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bangarh R, Khatana C, Kaur S, Sharma A, Kaushal A, Siwal SS, et al. Aberrant protein glycosylation: Implications on diagnosis and Immunotherapy. Biotechnol Adv. 2023;66: 108149. https://doi.org/10.1016/j.biotechadv.2023.108149.

    Article  CAS  PubMed  Google Scholar 

  61. Wang YW, Zuo JC, Chen C, Li XH. Post-translational modifications and immune responses in liver cancer. Front Immunol. 2023;14:1230465. https://doi.org/10.3389/fimmu.2023.1230465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mowen KA, David M. Unconventional post-translational modifications in immunological signaling. Nat Immunol. 2014;15:512–20. https://doi.org/10.1038/ni.2873.

    Article  CAS  PubMed  Google Scholar 

  63. Nagel T, Klaus F, Ibanez IG, Wege H, Lohse A, Meyer B. Fast and facile analysis of glycosylation and phosphorylation of fibrinogen from human plasma-correlation with liver cancer and liver cirrhosis. Anal Bioanal Chem. 2018;410:7965–77. https://doi.org/10.1007/s00216-018-1418-7.

    Article  CAS  PubMed  Google Scholar 

  64. Ren QN, Zhang H, Sun CY, Zhou YF, Yang XF, Long JW, et al. Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis. Hepatology. 2022;75:1123–38. https://doi.org/10.1002/hep.32120.

    Article  CAS  PubMed  Google Scholar 

  65. Mestareehi A, Abu-Farsakh N. Impact of protein phosphatase expressions on the prognosis of hepatocellular carcinoma patients. ACS Omega. 2024;9:10299–331. https://doi.org/10.1021/acsomega.3c07787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nishimagi A, Kobayashi M, Sugimoto K, Kofunato Y, Sato N, Haga J, et al. Aberrant phosphorylation of human LRH1 at serine 510 is predictable of hepatocellular carcinoma recurrence. Clin Exp Med. 2023;23:4985–95. https://doi.org/10.1007/s10238-023-01098-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang Y, Lao W, Yang K, Kong X, Li Y, Yu X, et al. SUV39H1 is a novel biomarker targeting oxidative phosphorylation in hepatitis B virus-associated hepatocellular carcinoma. BMC Cancer. 2023;23:1159. https://doi.org/10.1186/s12885-023-11633-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wu K, Yan M, Liu T, Wang Z, Duan Y, Xia Y, et al. Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function. Nat Cell Biol. 2023;25:714–25. https://doi.org/10.1038/s41556-023-01133-9.

    Article  CAS  PubMed  Google Scholar 

  69. Zhan M, Ding Y, Huang S, Liu Y, Xiao J, Yu H, et al. Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase. Nat Commun. 2023;14:3123. https://doi.org/10.1038/s41467-023-38753-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Xu D, Wang Z, Xia Y, Shao F, Xia W, Wei Y, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature. 2020;580:530–5. https://doi.org/10.1038/s41586-020-2183-2.

    Article  CAS  PubMed  Google Scholar 

  71. Feng J, Lu H, Ma W, Tian W, Lu Z, Yang H, et al. Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer. Protein Cell. 2022;13:825–41. https://doi.org/10.1007/s13238-022-00906-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wei CY, Zhu MX, Zhang PF, Huang XY, Wan JK, Yao XZ, et al. PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma. J Hepatol. 2022;77:163–76. https://doi.org/10.1016/j.jhep.2022.02.019.

    Article  CAS  PubMed  Google Scholar 

  73. Jiang N, Li W, Jiang S, Xie M, Liu R. Acetylation in pathogenesis: revealing emerging mechanisms and therapeutic prospects. Biomed Pharmacother. 2023;167: 115519. https://doi.org/10.1016/j.biopha.2023.115519.

    Article  CAS  PubMed  Google Scholar 

  74. Wu Z, Guan KL. Acetyl-CoA, protein acetylation, and liver cancer. Mol Cell. 2022;82:4196–8. https://doi.org/10.1016/j.molcel.2022.10.015.

    Article  CAS  PubMed  Google Scholar 

  75. Wang LT, Wang SN, Chiou SS, Liu KY, Chai CY, Chiang CM, et al. TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition and metastasis in liver cancer. Oncogene. 2019;38:518–32. https://doi.org/10.1038/s41388-018-0457-z.

    Article  CAS  PubMed  Google Scholar 

  76. Jing Z, Gao J, Li J, Niu F, Tian L, Nan P, et al. Acetylation-induced PCK isoenzyme transition promotes metabolic adaption of liver cancer to systemic therapy. Cancer Lett. 2021;519:46–62. https://doi.org/10.1016/j.canlet.2021.06.016.

    Article  CAS  PubMed  Google Scholar 

  77. Gu L, Zhu Y, Lin X, Tan X, Lu B, Li Y. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis. Oncogene. 2020;39:2437–49. https://doi.org/10.1038/s41388-020-1156-0.

    Article  CAS  PubMed  Google Scholar 

  78. Lin M, He J, Zhang X, Sun X, Dong W, Zhang R, et al. Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma. J Clin Invest. 2023. https://doi.org/10.1172/jci164528.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Hu H, Zhu W, Qin J, Chen M, Gong L, Li L, et al. Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology. 2017;65:515–28. https://doi.org/10.1002/hep.28887.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang T, Cui Y, Wu Y, Meng J, Han L, Zhang J, et al. Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma. Clin Transl Med. 2022;12: e852. https://doi.org/10.1002/ctm2.852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhou Y, Jia K, Wang S, Li Z, Li Y, Lu S, et al. Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GαS. Hepatology. 2023;77:1106–21. https://doi.org/10.1002/hep.32487.

    Article  CAS  PubMed  Google Scholar 

  82. Bi L, Ren Y, Feng M, Meng P, Wang Q, Chen W, et al. HDAC11 regulates glycolysis through the LKB1/AMPK signaling pathway to maintain hepatocellular carcinoma stemness. Cancer Res. 2021;81:2015–28. https://doi.org/10.1158/0008-5472.Can-20-3044.

    Article  CAS  PubMed  Google Scholar 

  83. Cai LY, Chen SJ, Xiao SH, Sun QJ, Ding CH, Zheng BN, et al. Targeting p300/CBP attenuates hepatocellular carcinoma progression through epigenetic regulation of metabolism. Cancer Res. 2021;81:860–72. https://doi.org/10.1158/0008-5472.Can-20-1323.

    Article  CAS  PubMed  Google Scholar 

  84. Xia H, Hui KM. Emergence of aspirin as a promising chemopreventive and chemotherapeutic agent for liver cancer. Cell Death Dis. 2017;8: e3112. https://doi.org/10.1038/cddis.2017.513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer. 2017;16:4. https://doi.org/10.1186/s12943-016-0572-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cheng Z, Li X, Ding J. Characteristics of liver cancer stem cells and clinical correlations. Cancer Lett. 2016;379:230–8. https://doi.org/10.1016/j.canlet.2015.07.041.

    Article  CAS  PubMed  Google Scholar 

  87. Xue M, Dong L, Zhang H, Li Y, Qiu K, Zhao Z, et al. METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation. J Hematol Oncol. 2024;17:7. https://doi.org/10.1186/s13045-024-01526-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sun JH, Luo Q, Liu LL, Song GB. Liver cancer stem cell markers: progression and therapeutic implications. World J Gastroenterol. 2016;22:3547–57. https://doi.org/10.3748/wjg.v22.i13.3547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang F, Gao Y, Xue S, Zhao L, Jiang H, Zhang T, et al. SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity. Nat Commun. 2023;14:5917. https://doi.org/10.1038/s41467-023-41593-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Raposo AE, Piller SC. Protein arginine methylation: an emerging regulator of the cell cycle. Cell Div. 2018;13:3. https://doi.org/10.1186/s13008-018-0036-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhao J, Adams A, Roberts B, O’Neil M, Vittal A, Schmitt T, et al. Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice. Hepatology. 2018;67:1109–26. https://doi.org/10.1002/hep.29587.

    Article  CAS  PubMed  Google Scholar 

  92. Lei Y, Han P, Chen Y, Wang H, Wang S, Wang M, et al. Protein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase A. Clin Transl Med. 2022;12: e686. https://doi.org/10.1002/ctm2.686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shi Y, Niu Y, Yuan Y, Li K, Zhong C, Qiu Z, et al. PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer. Nat Commun. 2023;14:1932. https://doi.org/10.1038/s41467-023-37542-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li Q, Zhang L, Yang Q, Li M, Pan X, Xu J, et al. Thymidine kinase 1 drives hepatocellular carcinoma in enzyme-dependent and-independent manners. Cell Metab. 2023;35:912-27.e7. https://doi.org/10.1016/j.cmet.2023.03.017.

    Article  CAS  PubMed  Google Scholar 

  95. Wang K, Luo L, Fu S, Wang M, Wang Z, Dong L, et al. PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma. Nat Commun. 2023;14:1011. https://doi.org/10.1038/s41467-023-36708-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Deng W, Ai J, Zhang W, Zhou Z, Li M, Yan L, et al. Arginine methylation of HSPA8 by PRMT9 inhibits ferroptosis to accelerate hepatitis B virus-associated hepatocellular carcinoma progression. J Transl Med. 2023;21:625. https://doi.org/10.1186/s12967-023-04408-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Thng DKH, Hooi L, Toh CCM, Lim JJ, Rajagopalan D, Syariff IQC, et al. Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer. Mol Oncol. 2023;17:2275–94. https://doi.org/10.1002/1878-0261.13417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu Z, Wang Q, Mao J, Wang K, Fang Z, Miao QR, et al. Comparative proteomic analysis of protein methylation provides insight into the resistance of hepatocellular carcinoma to 5-fluorouracil. J Proteom. 2020;219: 103738. https://doi.org/10.1016/j.jprot.2020.103738.

    Article  CAS  Google Scholar 

  99. Liu Q, Chen K, Liu Z, Huang Y, Zhao R, Wei L, et al. BORIS up-regulates OCT4 via histone methylation to promote cancer stem cell-like properties in human liver cancer cells. Cancer Lett. 2017;403:165–74. https://doi.org/10.1016/j.canlet.2017.06.017.

    Article  CAS  PubMed  Google Scholar 

  100. Guo M, Yao Z, Jiang C, Songyang Z, Gan L, Xiong Y. Three-dimensional and single-cell sequencing of liver cancer reveals comprehensive host-virus interactions in HBV infection. Front Immunol. 2023;14:1161522. https://doi.org/10.3389/fimmu.2023.1161522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. You H, Zhang N, Yu T, Ma L, Li Q, Wang X, et al. Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis. Br J Cancer. 2023;128:992–1004. https://doi.org/10.1038/s41416-022-02115-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang Y, Zhao M, Zhao L, Geng Y, Li G, Chen L, et al. HBx-induced HSPA8 stimulates HBV replication and suppresses ferroptosis to support liver cancer progression. Cancer Res. 2023;83:1048–61. https://doi.org/10.1158/0008-5472.Can-22-3169.

    Article  CAS  PubMed  Google Scholar 

  103. Yang L, Zou T, Chen Y, Zhao Y, Wu X, Li M, et al. Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma. Hepatol Int. 2022;16:741–54. https://doi.org/10.1007/s12072-022-10351-6.

    Article  PubMed  Google Scholar 

  104. Liu S, Koh SS, Lee CG. Hepatitis B virus X protein and hepatocarcinogenesis. Int J Mol Sci. 2016. https://doi.org/10.3390/ijms17060940.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Chen J, Li X, Ge C, Min J, Wang F. The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 2022;29:467–80. https://doi.org/10.1038/s41418-022-00941-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang W, Lu K, Jiang X, Wei Q, Zhu L, Wang X, et al. Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer. J Exp Clin Cancer Res. 2023;42:142. https://doi.org/10.1186/s13046-023-02720-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Huang Y, Wang S, Ke A, Guo K. Ferroptosis and its interaction with tumor immune microenvironment in liver cancer. Biochim Biophys Acta Rev Cancer. 2023;1878: 188848. https://doi.org/10.1016/j.bbcan.2022.188848.

    Article  CAS  PubMed  Google Scholar 

  108. Yang L, Tian S, Zheng X, Zhang M, Zhou X, Shang Y, et al. N6-methyladenosine RNA methylation in liver diseases: from mechanism to treatment. J Gastroenterol. 2023;58:718–33. https://doi.org/10.1007/s00535-023-02008-4.

    Article  CAS  PubMed  Google Scholar 

  109. Liu Y, Feng W, Wang Y, Wu B. Crosstalk between protein post-translational modifications and phase separation. Cell Commun Signal. 2024;22:110. https://doi.org/10.1186/s12964-023-01380-1.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Im H, Baek HJ, Yang E, Kim K, Oh SK, Lee JS, et al. ROS inhibits RORα degradation by decreasing its arginine methylation in liver cancer. Cancer Sci. 2023;114:187–200. https://doi.org/10.1111/cas.15595.

    Article  CAS  PubMed  Google Scholar 

  111. Blomme B, Van Steenkiste C, Callewaert N, Van Vlierberghe H. Alteration of protein glycosylation in liver diseases. J Hepatol. 2009;50:592–603. https://doi.org/10.1016/j.jhep.2008.12.010.

    Article  CAS  PubMed  Google Scholar 

  112. Zhang X, Liu H, Wang H, Zhao R, Lu Q, Liu Y, et al. B3galt5 deficiency attenuates hepatocellular carcinoma by suppressing mTOR/p70s6k-mediated glycolysis. Cell Mol Life Sci. 2022;80:8. https://doi.org/10.1007/s00018-022-04601-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cheng H, Wang S, Gao D, Yu K, Chen H, Huang Y, et al. Nucleotide sugar transporter SLC35A2 is involved in promoting hepatocellular carcinoma metastasis by regulating cellular glycosylation. Cell Oncol. 2023;46:283–97. https://doi.org/10.1007/s13402-022-00749-7.

    Article  CAS  Google Scholar 

  114. Nguyen AT, Chia J, Ros M, Hui KM, Saltel F, Bard F. Organelle specific O-glycosylation drives MMP14 activation, tumor growth, and metastasis. Cancer Cell. 2017;32:639-53.e6. https://doi.org/10.1016/j.ccell.2017.10.001.

    Article  CAS  PubMed  Google Scholar 

  115. Li J, Liu X, Peng B, Feng T, Zhou W, Meng L, et al. O-GlcNAc has crosstalk with ADP-ribosylation via PARG. J Biol Chem. 2023;299: 105354. https://doi.org/10.1016/j.jbc.2023.105354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhou P, Chang WY, Gong DA, Xia J, Chen W, Huang LY, et al. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. Cell Metab. 2023;35:1961-75.e6. https://doi.org/10.1016/j.cmet.2023.09.009.

    Article  CAS  PubMed  Google Scholar 

  117. Xiang J, Chen C, Liu R, Gou D, Chang L, Deng H, et al. Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation. J Clin Invest. 2021. https://doi.org/10.1172/jci144703.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zou X, Lu J, Deng Y, Liu Q, Yan X, Cui Y, et al. ST6GAL1 inhibits metastasis of hepatocellular carcinoma via modulating sialylation of MCAM on cell surface. Oncogene. 2023;42:516–29. https://doi.org/10.1038/s41388-022-02571-9.

    Article  CAS  PubMed  Google Scholar 

  119. Liu L, Pan Y, Zhao C, Huang P, Chen X, Rao L. Boosting checkpoint immunotherapy with biomaterials. ACS Nano. 2023;17:3225–58. https://doi.org/10.1021/acsnano.2c11691.

    Article  CAS  PubMed  Google Scholar 

  120. Khalilov R, Bakishzade A, Nasibova A. Future prospects of biomaterials in nanomedicine. Adv Biol Earth Sci. 2023. https://doi.org/10.62476/abes.9s5.

    Article  Google Scholar 

  121. Rosic G, Selakovic D, Omarova S. Cancer signaling, cell/gene therapy, diagnosis and role of nanobiomaterials. Adv Biol Earth Sci. 2024. https://doi.org/10.62476/abes9s11.

    Article  Google Scholar 

  122. Huseynov E, Khalilov R, Mohamed AJ. Novel nanomaterials for hepatobiliary diseases treatment and future perspectives. Adv Biol Earth Sci. 2024. https://doi.org/10.2476/abes9s81.

    Article  Google Scholar 

  123. Salahshour P. Nanobiomaterials/bioinks based scaffolds in 3d bioprinting for tissue engineering and artificial human organs. Adv Biol Earth Sci. 2024;9:97–104. https://doi.org/10.2476/abes9s97.

    Article  Google Scholar 

  124. Erdil N. Cardiovascular disease, signaling, gene/cell therapy and advanced nanobiomaterials. Adv Biol Earth Sci. 2024;9:58–80.

    Article  Google Scholar 

  125. Xu M, Yang L, Lin Y, Lu Y, Bi X, Jiang T, et al. Emerging nanobiotechnology for precise theranostics of hepatocellular carcinoma. J Nanobiotechnology. 2022;20:427. https://doi.org/10.1186/s12951-022-01615-2.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Chi X, Liu K, Luo X, Yin Z, Lin H, Gao J. Recent advances of nanomedicines for liver cancer therapy. J Mater Chem B. 2020;8:3747–71. https://doi.org/10.1039/c9tb02871d.

    Article  CAS  PubMed  Google Scholar 

  127. Shao D, Li J, Zheng X, Pan Y, Wang Z, Zhang M, et al. Janus “nano-bullets” for magnetic targeting liver cancer chemotherapy. Biomaterials. 2016;100:118–33. https://doi.org/10.1016/j.biomaterials.2016.05.030.

    Article  CAS  PubMed  Google Scholar 

  128. Han Q, Du L, Zhu L, Yu D. Review of the application of dual drug delivery nanotheranostic agents in the diagnosis and treatment of liver cancer. Molecules. 2023. https://doi.org/10.3390/molecules28207004.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wu S, Fan K, Yang Q, Chen Z, Hou Y, Zou Y, et al. Smart nanoparticles and microbeads for interventional embolization therapy of liver cancer: state of the art. J Nanobiotechnology. 2023;21:42. https://doi.org/10.1186/s12951-023-01804-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kong FH, Ye QF, Miao XY, Liu X, Huang SQ, Xiong L, et al. Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma. Theranostics. 2021;11:5464–90. https://doi.org/10.7150/thno.54822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by Natural Science Foundation exploration project of Zhejiang Province (LY21H030010), National Natural Science Foundation of China (82170673), and the Natural Science Foundation of Zhejiang Province (LQ20H030006).

Author information

Author notes

  1. Yu Zhang and Weihao Xu have contributed equally to this work.

Authors and Affiliations

  1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Yu Zhang, Weihao Xu, Chuanhui Peng, Shenli Ren & Cheng Zhang

Authors
  1. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weihao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuanhui Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shenli Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the authors contributed to the manuscript and reviewed and approved it as presented here. Yu Zhang and Weihao Xu contributed to the concept of the review and writing the manuscript. Chuanhui Peng and Shenli Ren, designed the figure. Cheng Zhang aided in revising the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Cheng Zhang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

All authors declare no competing interests related to this review.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Xu, W., Peng, C. et al. Intricate effects of post-translational modifications in liver cancer: mechanisms to clinical applications. J Transl Med 22, 651 (2024). https://doi.org/10.1186/s12967-024-05455-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12967-024-05455-6

Keywords

Journal of Translational Medicine

ISSN: 1479-5876

Contact us