Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol. 2020;72:250–61.
Google Scholar
Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol. 2023;20:864–84.
Google Scholar
Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, et al. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67:302–9.
Google Scholar
Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68:526–49.
Google Scholar
Petrick JL, Kelly SP, Altekruse SF, McGlynn KA, Rosenberg PS. Future of Hepatocellular Carcinoma Incidence in the United States Forecast Through 2030. J Clin Oncol. 2016;34:1787–94.
Google Scholar
Sangro B, Argemi J, Ronot M, Paradis V, Meyer T, Mazzaferro V, et al. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol. 2025;82:315–74.
Google Scholar
Lin P, Qin Q, Gan X, Pang J, Wen R, He Y, et al. Integrating single-cell and bulk RNA sequencing data to characterize the heterogeneity of glycan-lipid metabolism polarization in hepatocellular carcinoma. J Transl Med. 2025;23:358.
Google Scholar
Safri F, Nguyen R, Zerehpooshnesfchi S, George J, Qiao L. Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications. Cancer Gene Ther. 2024;31:1105–12.
Google Scholar
Losic B, Craig AJ, Villacorta-Martin C, Martins-Filho SN, Akers N, Chen X, et al. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat Commun. 2020;11:291.
Google Scholar
Lee Y, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology. 2023;78:319–62.
Google Scholar
Chon YE, Park SY, Hong HP, Son D, Lee J, Yoon E, et al. Hepatocellular carcinoma incidence is decreasing in Korea but increasing in the very elderly. Clin Mol Hepatol. 2023;29:120–34.
Google Scholar
McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology. 2021;73:4–13.
Google Scholar
Péneau C, Imbeaud S, La Bella T, Hirsch TZ, Caruso S, Calderaro J, et al. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Gut. 2022;71:616–26.
Google Scholar
Wang Y, Yu D, Mei Y, Fu Z, Lin J, Wu D, et al. Long-read sequencing reveals HBV integration patterns and oncogenic impact on early-onset hepatocellular carcinoma. Genome Res. 2025. https://doi.org/10.1101/gr.279889.124.
Hama N, Totoki Y, Miura F, Tatsuno K, Saito-Adachi M, Nakamura H, et al. Epigenetic landscape influences the liver cancer genome architecture. Nat Commun. 2018;9:1643.
Google Scholar
Locatelli M, Quivy J-P, Chapus F, Michelet M, Fresquet J, Maadadi S, et al. HIRA Supports Hepatitis B Virus Minichromosome Establishment and Transcriptional Activity in Infected Hepatocytes. Cell Mol Gastroenterol Hepatol. 2022;14:527–51.
Google Scholar
Tanaka H, Diogo Dias J, Jay B, Kita S, Sasaki M, Takeda H, et al. Structural basis of the hepatitis B virus X protein in complex with DDB1. Proc Natl Acad Sci USA. 2025;122. https://doi.org/10.1073/pnas.2421325122.
Decorsière A, Mueller H, van Breugel PC, Abdul F, Gerossier L, Beran RK, et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature. 2016;531:386–9.
Google Scholar
Yang B, Li B, Jia L, Jiang Y, Wang X, Jiang S, et al. 3D landscape of Hepatitis B virus interactions with human chromatins. Cell Discov. 2020;6:95.
Google Scholar
Liu Z, Naz W, Yousaf T, Sun J, Wu Q, Guo M, et al. Viral-Track integrated single-cell RNA-sequencing reveals HBV lymphotropism and immunosuppressive microenvironment in HBV-associated hepatocellular carcinoma. Commun Biol. 2025;8:1030.
Google Scholar
Zanotti S, Boot GF, Coto-Llerena M, Gallon J, Hess GF, Soysal SD et al. The Role of Chronic Liver Diseases in the Emergence and Recurrence of Hepatocellular Carcinoma: An Omics Perspective. Front Med. 2022;9. https://doi.org/10.3389/fmed.2022.888850.
Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2016;2:16018.
Google Scholar
Mason WS, Jilbert AR, Litwin S. Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver. Viruses. 2021;13:210.
Google Scholar
D’souza S, Lau KC, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol. 2020;26:5759–83.
Google Scholar
Bertoletti A, Kennedy PT. The immune tolerant phase of chronic HBV infection: new perspectives on an old concept. Cell Mol Immunol. 2015;12:258–63.
Google Scholar
Ringehan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philos Philos Trans R Soc B Biol Sci. 2017;372:20160274.
Google Scholar
Guerrieri F, Belloni L, Pediconi N, Levrero M. Molecular Mechanisms of HBV-Associated Hepatocarcinogenesis. Semin Liver Dis. 2013;33:147–56.
Google Scholar
Sung W-K, Zheng H, Li S, Chen R, Liu X, Li Y, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012;44:765–9.
Google Scholar
Zhao L-H, Liu X, Yan H-X, Li W-Y, Zeng X, Yang Y, et al. Erratum: Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma. Nat Commun. 2016;7:13591.
Google Scholar
Zoller H, Tilg H. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Metabolism. 2016;65:1151–60.
Google Scholar
Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma: A Weighty Connection. Hepatology. 2010;51:1820–32.
Google Scholar
Marengo A, Rosso C, Bugianesi E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu Rev Med. 2016;67:103–17.
Google Scholar
Takeda H, Takai A, Inuzuka T, Marusawa H. Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis. J Gastroenterol. 2017;52:26–38.
Google Scholar
Gallon J, Coto-Llerena M, Ercan C, Bianco G, Paradiso V, Nuciforo S, et al. Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma. Mol Oncol. 2022;16:665–82.
Google Scholar
Graupera I, Isus L, Coll M, Pose E, Díaz A, Vallverdú J, et al. Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure. JHEP Rep. 2022;4:100482.
Google Scholar
Silwal A, Reese B, Patel B, Li Y, Kolev MV, La-Beck NM, et al. TP53 Codon 72 Polymorphism Impacts Macrophage Activation through Reactive Oxygen Species–Dependent Cell Signaling Alterations. J Immunol. 2024;213:1844–57.
Google Scholar
Tozatto-Maio K, Girot R, Ly ID, Silva Pinto AC, Rocha V, Fernandes F, et al. Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease. Front Immunol. 2020;11. https://doi.org/10.3389/fimmu.2020.02041.
Mittal P, Roberts CWM. The SWI/SNF complex in cancer — biology, biomarkers and therapy. Nat Rev Clin Oncol. 2020;17:435–48.
Google Scholar
Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet. 2017;49:296–302.
Google Scholar
Zhao Q-Y, Lei P-J, Zhang X, Zheng J-Y, Wang H-Y, Zhao J, et al. Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model. Clin Epigenet. 2016;8:34.
Google Scholar
Gopi LK, Kidder BL. Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains. Nat Commun. 2021;12:1419.
Google Scholar
Bayo J, Fiore EJ, Dominguez LM, Real A, Malvicini M, Rizzo M, et al. A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets. J Hepatol. 2019;71:78–90.
Google Scholar
Davletgildeeva AT, Kuznetsov NA. The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level. Biomolecules. 2024;14:1117.
Google Scholar
Claveria-Cabello A, Colyn L, Arechederra M, Urman JM, Berasain C, Avila MA, et al. Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target? Cells. 2020;9:2321.
Google Scholar
Song M-A, Tiirikainen M, Kwee S, Okimoto G, Yu H, Wong LL. Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma. PLoS One. 2013;8:e55761.
Google Scholar
Khan R, Zakir U, Naqvi F-U-H. Aberrant DNA methylation in human hepatocellular carcinoma. Pak J Med Dent. 2021;10:013. https://doi.org/10.36283/PJMD10-2/013.
Google Scholar
Sun D, Gan X, Liu L, Yang Y, Ding D, Li W, et al. DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334. Cell Death Dis. 2022;13:446.
Google Scholar
Revill K, Wang T, Lachenmayer A, Kojima K, Harrington A, Li J, et al. Genome-Wide Methylation Analysis and Epigenetic Unmasking Identify Tumor Suppressor Genes in Hepatocellular Carcinoma. Gastroenterology. 2013;145:1424–1435.e25.
Google Scholar
Zhang D, Guo S, Schrodi SJ. Mechanisms of DNA Methylation in Virus-Host Interaction in Hepatitis B Infection: Pathogenesis and Oncogenetic Properties. Int J Mol Sci. 2021;22:9858.
Google Scholar
Zheng Y, Huang Q, Ding Z, Liu T, Xue C, Sang X, et al. Genome-wide DNA methylation analysis identifies candidate epigenetic markers and drivers of hepatocellular carcinoma. Brief Bioinform. 2018;19:101–8. https://doi.org/10.1093/bib/bbw094.
Google Scholar
Wu X-M, Xi Z-F, Lu J, Wang X-Z, Zhang T-Q, Huang X-Y, et al. Genetic single nucleotide polymorphisms (GSNPs) in the DNA repair genes and hepatocellular carcinoma related to aflatoxin B1 among Guangxiese population. In: Genetic Polymorphisms. IntechOpen; 2017. https://doi.org/10.5772/intechopen.69530.
Nahon P, Zucman-Rossi J. Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol. 2012;57:663–74.
Google Scholar
Yang T-H, Chan C, Yang P-J, Huang Y-H, Lee M-H. Genetic Susceptibility to Hepatocellular Carcinoma in Patients with Chronic Hepatitis Virus Infection. Viruses. 2023;15:559.
Google Scholar
Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.
Google Scholar
Niu Z-S, Niu X-J, Wang W-H. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol. 2016;22:9069.
Google Scholar
Long XD, Ma Y, Wei YP, Deng ZL. The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China. Hepatol Res. 2006;36:48–55. https://doi.org/10.1016/j.hepres.2006.06.004.
Google Scholar
Chu Y-J, Yang H-I, Wu H-C, Lee M-H, Liu J, Wang L-Y, et al. Aflatoxin B1 exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption. Eur J Cancer. 2018;94:37–46.
Google Scholar
Wang Z, Wang W, Wang L. Epigenetic regulation of covalently closed circular DNA minichromosome in hepatitis B virus infection. Biophys Rep. 2020;6:115–26.
Google Scholar
Dandri M. Epigenetic modulation in chronic hepatitis B virus infection. Semin Immunopathol. 2020;42:173–85.
Google Scholar
Xia Y, Guo H. Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antivir Res. 2020;180:104824.
Google Scholar
Tropberger P, Mercier A, Robinson M, Zhong W, Ganem DE, Holdorf M. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proc Natl Acad Sci USA. 2015;112:E5715–E5724. https://doi.org/10.1073/pnas.1518090112.
Google Scholar
Hong X, Kim ES, Guo H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B. Hepatology. 2017;66:2066–77.
Google Scholar
Cougot D, Wu Y, Cairo S, Caramel J, Renard C-A, Lévy L, et al. The Hepatitis B Virus X Protein Functionally Interacts with CREB-binding Protein/p300 in the Regulation of CREB-mediated Transcription. J Biol Chem. 2007;282:4277–87.
Google Scholar
Chong CK, Cheng CYS, Tsoi SYJ, Huang F-Y, Liu F, Fung J, et al. HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA. Sci Rep. 2020;10:802.
Google Scholar
Belloni L, Pollicino T, De Nicola F, Guerrieri F, Raffa G, Fanciulli M, et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci USA. 2009;106:19975–9.
Google Scholar
Huang J, Wan D, Li J, Chen H, Huang K, Zheng L. Histone acetyltransferase PCAF regulates inflammatory molecules in the development of renal injury. Epigenetics. 2015;10:62–71.
Google Scholar
Scott-Browne JP, López-Moyado IF, Trifari S, Wong V, Chavez L, Rao A, et al. Dynamic Changes in Chromatin Accessibility Occur in CD8+T Cells Responding to Viral Infection. Immunity. 2016;45:1327–40.
Google Scholar
Cui A, Ding D, Li Y. Regulation of Hepatic Metabolism and Cell Growth by the ATF/CREB Family of Transcription Factors. Diabetes. 2021;70:653–64.
Google Scholar
Studach LL, Menne S, Cairo S, Buendia MA, Hullinger RL, Lefrançois L, et al. Subset of Suz12/PRC2 target genes is activated during hepatitis B virus replication and liver carcinogenesis associated with HBV X protein. Hepatology. 2012;56:1240–51.
Google Scholar
Andrisani O. Epigenetic mechanisms in hepatitis B virus-associated hepatocellular carcinoma. Hepatoma Res. 2021;7. https://doi.org/10.20517/2394-5079.2020.83.
Tan X, Xun L, Yin Q, Chen C, Zhang T, Shen T. Epigenetic Modifications in HBV-Related Hepatocellular Carcinoma. J Viral Hepat. 2025;32. https://doi.org/10.1111/jvh.14044.
Elsharkawy AM, Oakley F, Lin F, Packham G, Mann DA, Mann J. The NF-κB p50:p50:HDAC-1 repressor complex orchestrates transcriptional inhibition of multiple pro-inflammatory genes. J Hepatol. 2010;53:519–27.
Google Scholar
Raynal NJ-M, Si J, Taby RF, Gharibyan V, Ahmed S, Jelinek J, et al. DNA Methylation Does Not Stably Lock Gene Expression but Instead Serves as a Molecular Mark for Gene Silencing Memory. Cancer Res. 2012;72:1170–81.
Google Scholar
Benn J, Schneider RJ. Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc Natl Acad Sci USA. 1995;92:11215–9.
Google Scholar
Chan C, Thurnherr T, Wang J, Gallart-Palau X, Sze SK, Rozen S, et al. Global re-wiring of p53 transcription regulation by the hepatitis B virus X protein. Mol Oncol. 2016;10:1183–95.
Google Scholar
Cameron EE, Bachman KE, Myöhänen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–7.
Google Scholar
Lee S, Lee M-J, Zhang J, Yu G-R, Kim D-G. C-terminal-truncated HBV X promotes hepato-oncogenesis through inhibition of tumor-suppressive β-catenin/BAMBI signaling. Exp Mol Med. 2016;48:e275–e275.
Google Scholar
Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases. Cell. 1996;87:953–9.
Google Scholar
Murphy CM, Xu Y, Li F, Nio K, Reszka-Blanco N, Li X, et al. Hepatitis B Virus X Protein Promotes Degradation of SMC5/6 to Enhance HBV Replication. Cell Rep. 2016;16:2846–54.
Google Scholar
Sekiba K, Otsuka M, Funato K, Miyakawa Y, Tanaka E, Seimiya T, et al. HBx-induced degradation of Smc5/6 complex impairs homologous recombination-mediated repair of damaged DNA. J Hepatol. 2022;76:53–62.
Google Scholar
Bächer J, Allweiss L, Dandri M. SMC5/6-Mediated Transcriptional Regulation of Hepatitis B Virus and Its Therapeutic Potential. Viruses. 2024;16:1667.
Google Scholar
Furuta M, Tanaka H, Shiraishi Y, Uchida T, Imamura M, Fujimoto A, et al. Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers. Oncotarget. 2018;9:25075–88.
Google Scholar
Tian Y, Ou JJ. Genetic and epigenetic alterations in hepatitis B virus-associated hepatocellular carcinoma. Virol Sin. 2015;30:85–91.
Google Scholar
Boyault S, Rickman DS, de Reyniès A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52.
Google Scholar
Wang S, Zhang C, Hasson D, Desai A, SenBanerjee S, Magnani E, et al. Epigenetic Compensation Promotes Liver Regeneration. Dev Cell. 2019;50:43–56.e6.
Google Scholar
Inoue A, Jiang L, Lu F, Suzuki T, Zhang Y. Maternal H3K27me3 controls DNA methylation-independent imprinting. Nature. 2017;547:419–24.
Google Scholar
Yang B, Guo M, Herman JG, Clark DP. Aberrant Promoter Methylation Profiles of Tumor Suppressor Genes in Hepatocellular Carcinoma. Am J Pathol. 2003;163:1101–7.
Google Scholar
Villanueva A, Portela A, Sayols S, Battiston C, Hoshida Y, Méndez-González J, et al. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology. 2015;61:1945–56.
Google Scholar
Hernandez-Vargas H, Lambert M-P, Le Calvez-Kelm F, Gouysse G, McKay-Chopin S, Tavtigian SV, et al. Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures with Potential as Clinical Predictors. PLoS One. 2010;5:e9749.
Google Scholar
Rembiałkowska N, Rekiel K, Urbanowicz P, Mamala M, Marczuk K, Wojtaszek M, et al. Epigenetic Dysregulation in Cancer: Implications for Gene Expression and DNA Repair-Associated Pathways. Int J Mol Sci. 2025;26:6531.
Google Scholar
Herman JG, Baylin SB. Promoter-region hypermethylation and gene silencing in human cancer. Curr Top Microbiol Immunol. 2000;249:35–54. https://doi.org/10.1007/978-3-642-59696-4_3.
Google Scholar
Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics. 2009;1:239–59.
Google Scholar
Oh B-K, Kim H, Park H-J, Shim Y-H, Choi J, Park C, et al. DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. Int J Mol Med. 2007;20:65–73.
Google Scholar
Gao Q, Zhu H, Dong L, Shi W, Chen R, Song Z, et al. Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma. Cell. 2019;179:561–577.e22.
Google Scholar
Liu C, Liu L, Chen X, Shen J, Shan J, Xu Y, et al. Decrease of 5-Hydroxymethylcytosine Is Associated with Progression of Hepatocellular Carcinoma through Downregulation of TET1. PLoS One. 2013;8:e62828.
Google Scholar
Lubecka K, Flower K, Beetch M, Qiu J, Kurzava L, Buvala H, et al. Loci-specific differences in blood DNA methylation in HBV-negative populations at risk for hepatocellular carcinoma development. Epigenetics. 2018;13:605–26.
Google Scholar
Zhang Y, Mao R, Yan R, Cai D, Zhang Y, Zhu H, et al. Transcription of Hepatitis B Virus Covalently Closed Circular DNA Is Regulated by CpG Methylation during Chronic Infection. PLoS One. 2014;9:e110442.
Google Scholar
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med. 2010;49:1603–16.
Google Scholar
Um T-H, Kim H, Oh B-K, Kim MS, Kim KS, Jung G, et al. Aberrant CpG island hypermethylation in dysplastic nodules and early HCC of hepatitis B virus-related human multistep hepatocarcinogenesis. J Hepatol. 2011;54:939–47.
Google Scholar
Zekri A-RN, Bahnasy AA, Shoeab FEM, Mohamed WS, El-Dahshan DH, Ali FT, et al. Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma. J Adv Res. 2014;5:27–40.
Google Scholar
Qian Y, Wang J-W, Fang Y, Yuan X-D, Fan Y-C, Gao S, et al. Measurement of Cyclin D2 (CCND2) Gene Promoter Methylation in Plasma and Peripheral Blood Mononuclear Cells and Alpha-Fetoprotein Levels in Patients with Hepatitis B Virus-Associated Hepatocellular Carcinoma. Med Sci Monit. 2020;26. https://doi.org/10.12659/MSM.927444.
Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, et al. Hepatitis B Virus Replication Is Regulated by the Acetylation Status of Hepatitis B Virus cccDNA-Bound H3 and H4 Histones. Gastroenterology. 2006;130:823–37.
Google Scholar
Rivière L, Gerossier L, Ducroux A, Dion S, Deng Q, Michel M-L, et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase. J Hepatol. 2015;63:1093–102.
Google Scholar
Yan J, Chen S-AA, Local A, Liu T, Qiu Y, Dorighi KM, et al. Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell Res. 2018;28:204–20.
Google Scholar
Statello L, Guo C-J, Chen L-L, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22:96–118.
Google Scholar
Huo X, Han S, Wu G, Latchoumanin O, Zhou G, Hebbard L, et al. Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells. Mol Cancer. 2017;16:165.
Google Scholar
Huang Z, Zhou J-K, Peng Y, He W, Huang C. The role of long noncoding RNAs in hepatocellular carcinoma. Mol Cancer. 2020;19:77.
Google Scholar
Sun Q, Hao Q, Prasanth KV. Nuclear Long Noncoding RNAs: Key Regulators of Gene Expression. Trends Genet. 2018;34:142–57.
Google Scholar
Mohr A, Mott J. Overview of MicroRNA Biology. Semin Liver Dis. 2015;35:003–11.
Google Scholar
Zhang Q, Matsuura K, Kleiner DE, Zamboni F, Alter HJ, Farci P. Analysis of long noncoding RNA expression in hepatocellular carcinoma of different viral etiology. J Transl Med. 2016;14:328.
Google Scholar
Yu J, Zhang H, Zhang Y, Zhang X. Integrated Analysis of the Altered lncRNA, microRNA, and mRNA Expression in HBV-Positive Hepatocellular Carcinoma. Life. 2022;12:701.
Google Scholar
Singh AK, Rooge SB, Varshney A, Vasudevan M, Bhardwaj A, Venugopal SK, et al. Global microRNA expression profiling in the liver biopsies of hepatitis B virus–infected patients suggests specific microRNA signatures for viral persistence and hepatocellular injury. Hepatology. 2018;67:1695–709.
Google Scholar
Xu J, An P, Winkler CA, Yu Y. Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets. Front Oncol. 2020;10. https://doi.org/10.3389/fonc.2020.01271.
Ramakrishnan K, Vishwakarma R, Dev RR, Raju R, Rehman N. Etiologically Significant microRNAs in Hepatitis B Virus-Induced Hepatocellular Carcinoma. OMICS. 2024;28:280–90.
Google Scholar
Li CH, Xu F, Chow S, Feng L, Yin D, Ng TB, et al. Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression. Eur J Cancer. 2014;50:2560–9.
Google Scholar
Meng F, Henson R, Wehbe–Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology. 2007;133:647–58.
Google Scholar
Tsai W-C, Hsu S-D, Hsu C-S, Lai T-C, Chen S-J, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122:2884–97.
Google Scholar
Jopling CL. Regulation of hepatitis C virus by microRNA-122. Biochem Soc Trans. 2008;36:1220–3.
Google Scholar
Huang J, Wang Y, Guo Y, Sun S. Down-Regulated MicroRNA-152 Induces Aberrant DNA Methylation in Hepatitis B Virus–Related Hepatocellular Carcinoma by Targeting DNA Methyltransferase 1. Hepatology. 2010;52:60–70.
Google Scholar
Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, et al. MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer. N Engl J Med. 2009;361:1437–47.
Google Scholar
Schmitt AM, Chang HY. Long Noncoding RNAs in Cancer Pathways. Cancer Cell. 2016;29:452–63.
Google Scholar
Samudh N, Shrilall C, Arbuthnot P, Bloom K, Ely A. Diversity of Dysregulated Long Non-Coding RNAs in HBV-Related Hepatocellular Carcinoma. Front Immunol. 2022;13. https://doi.org/10.3389/fimmu.2022.834650.
Alfano V, Zeisel MB, Levrero M, Guerrieri F. The lncRNAs in HBV-Related HCCs: Targeting Chromatin Dynamics and Beyond. Cancers. 2021;13:3115.
Google Scholar
Feng J, Yang G, Liu Y, Gao Y, Zhao M, Bu Y, et al. LncRNA PCNAP1 modulates hepatitis B virus replication and enhances tumor growth of liver cancer. Theranostics. 2019;9:5227–45.
Google Scholar
Salerno D, Chiodo L, Alfano V, Floriot O, Cottone G, Paturel A, et al. Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription. Gut. 2020;69:2016–24.
Google Scholar
Hu J-J, Song W, Zhang S-D, Shen X-H, Qiu X-M, Wu H-Z, et al. HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling. Sci Rep. 2016;6:23521.
Google Scholar
Zhang H, Diab A, Fan H, Mani SKK, Hullinger R, Merle P, et al. PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus–Induced Liver Carcinogenesis. Cancer Res. 2015;75:2363–74.
Google Scholar
Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA. Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. JHEP Rep. 2020;2:100167.
Google Scholar
Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Nakagama H, et al. Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells. Mol Ther. 2018;26:1840–54.
Google Scholar
Jones PA, Issa J-PJ, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17:630–41.
Google Scholar
Dawson MA, Kouzarides T. Cancer Epigenetics: From Mechanism to Therapy. Cell. 2012;150:12–27.
Google Scholar
Topper MJ, Vaz M, Chiappinelli KB, DeStefano Shields CE, Niknafs N, Yen R-WC, et al. Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell. 2017;171:1284–1300.e21.
Google Scholar
Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell. 2015;162:961–73.
Google Scholar
Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell. 2017;169:361.
Google Scholar
Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immune-oncology. Nat Rev Cancer. 2019;19:151–61.
Google Scholar
Liu M, Zhang L, Li H, Hinoue T, Zhou W, Ohtani H, et al. Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor Guadecitabine (SGI-110) in Hepatocellular Carcinoma. Hepatology. 2018;68:1412–28.
Google Scholar
Hu C, Liu X, Zeng Y, Liu J, Wu F. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin Epigenet. 2021;13:166.
Google Scholar
Zhang M, Zhou X, Li Z, Zhao T, Miao Y, Liu S, et al. Decitabine regulates the resistance of HCC to sorafenib through demethylation. Clin Epigenet. 2025;17:120.
Google Scholar
Jueliger S, Lyons J, Cannito S, Pata I, Pata P, Shkolnaya M, et al. Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma. Epigenetics. 2016;11:709–20.
Google Scholar
Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Mol Oncol. 2015;9:1799–814.
Google Scholar
Hlady RA, Robertson KD. A Three-Pronged Epigenetic Approach to the Treatment of Hepatocellular Carcinoma. Hepatology. 2018;68:1226–8.
Google Scholar
Ruzic D, Djoković N, Srdić-Rajić T, Echeverria C, Nikolic K, Santibanez JF. Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. Pharmaceutics. 2022;14:209.
Google Scholar
Hao D, Deng F, Shi H, Wang H, Xiao F, Sun C, et al. In vivo inhibitory effect of suberoylanilide hydroxamic acid combined with sorafenib on human hepatocellular carcinoma cells. Brazilian J Pharmaceutical Sci. 2020; 56. https://doi.org/10.1590/s2175-97902019000318254.
Freese K, Seitz T, Dietrich P, Lee SML, Thasler WE, Bosserhoff A, et al. Histone Deacetylase Expressions in Hepatocellular Carcinoma and Functional Effects of Histone Deacetylase Inhibitors on Liver Cancer Cells In Vitro. Cancers. 2019;11:1587.
Google Scholar
Suraweera A, O’Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol. 2018;8. https://doi.org/10.3389/fonc.2018.00092.
Zeisel MB, Guerrieri F, Levrero M. Host Epigenetic Alterations and Hepatitis B Virus-Associated Hepatocellular Carcinoma. J Clin Med. 2021;10:1715.
Google Scholar
Kim J, Ha J, Song C, Sajjad MA, Kalsoom F, Kwon H, et al. Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA. Front Cell Infect Microbiol. 2025;15. https://doi.org/10.3389/fcimb.2025.1537929.
Castelló-Uribe B, López-Pascual A, Elurbide J, Adán-Villaescusa E, Valbuena-Goiricelaya E, Martinez-Perez LA, et al. Expression landscape of epigenetic genes in human hepatocellular carcinoma. J Physiol Biochem. 2025;81:699–727.
Google Scholar
van der Ree MH, van der Meer AJ, de Bruijne J, Maan R, van Vliet A, Welzel TM, et al. Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients. Antivir Res. 2014;111:53–59.
Google Scholar
Seyhan AA. Trials and Tribulations of MicroRNA Therapeutics. Int J Mol Sci. 2024;25:1469.
Google Scholar
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.
Google Scholar
Zhang Y, Cao W, Wang S, Zhang L, Li X, Zhang Z, et al. Epigenetic modification of hepatitis B virus infection and related hepatocellular carcinoma. Virulence. 2024;15. https://doi.org/10.1080/21505594.2024.2421231.
Hong YK, Li Y, Pandit H, Li S, Pulliam Z, Zheng Q, et al. Epigenetic modulation enhances immunotherapy for hepatocellular carcinoma. Cell Immunol. 2019;336:66–74.
Google Scholar
