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MYC in liver cancer: mechanisms and targeted therapy opportunities

Oncogene volume 42, pages 3303–3318 (2023)Cite this article

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Abstract

MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.

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Fig. 1: A schematic of multiple domains of MYC.
Fig. 2: Copy number variation in the genome of MYC in hepatocellular carcinoma.
Fig. 3: MYC in liver cancer.
Fig. 4: Several potential strategies for targeting MYC in liver cancer.

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References

  1. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4–13.

    Article  CAS  PubMed  Google Scholar 

  2. Nault JC, Villanueva A. Biomarkers for hepatobiliary cancers. Hepatology. 2021;73:115–27.

    Article  PubMed  Google Scholar 

  3. Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152:745–61.

    Article  CAS  PubMed  Google Scholar 

  4. Chen H, Guan Q, Guo H, Miao L, Zhuo Z. The genetic changes of hepatoblastoma. Front Oncol. 2021;11:690641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Bba-Rev Cancer. 2020;1873:188314.

    CAS  Google Scholar 

  6. Dang CV. MYC on the path to cancer. Cell. 2012;149:22–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. 2008;8:976–90.

    Article  CAS  PubMed  Google Scholar 

  8. Krishnan MS, Rajan KA, Park J, Arjunan V, Garcia MF, Bermudez A, et al. Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers. Hepatology. 2021;73:2342–60.

    Article  CAS  PubMed  Google Scholar 

  9. Lourenco C, Resetca D, Redel C, Lin P, MacDonald AS, Ciaccio R, et al. MYC protein interactors in gene transcription and cancer. Nat Rev Cancer. 2021;21:579–91.

    Article  CAS  PubMed  Google Scholar 

  10. Fladvad M, Zhou K, Moshref A, Pursglove S, Safsten P, Sunnerhagen M. N and C-terminal sub-regions in the c-Myc transactivation region and their joint role in creating versatility in folding and binding. J Mol Biol. 2005;346:175–89.

    Article  CAS  PubMed  Google Scholar 

  11. Kalkat M, Resetca D, Lourenco C, Chan PK, Wei Y, Shiah YJ, et al. MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis. Mol Cell. 2018;72:836–48.

    Article  CAS  PubMed  Google Scholar 

  12. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Gene Dev. 2000;14:2501–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Farrell AS, Sears RC. MYC degradation. Csh Perspect Med. 2014;4:a014365.

    Google Scholar 

  14. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle. 2004;3:1133–7.

    Article  CAS  PubMed  Google Scholar 

  15. Sun XX, He X, Yin L, Komada M, Sears RC, Dai MS. The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proc Natl Acad Sci USA. 2015;112:3734–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, et al. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007;9:765–74.

    Article  CAS  PubMed  Google Scholar 

  17. Richards MW, Burgess SG, Poon E, Carstensen A, Eilers M, Chesler L, et al. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. P Natl Acad Sci USA. 2016;113:13726–31.

    Article  CAS  Google Scholar 

  18. Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, et al. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med. 2016;22:744–53.

    Article  CAS  PubMed  Google Scholar 

  19. Farrell AS, Pelz C, Wang X, Daniel CJ, Wang Z, Su Y, et al. Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis. Mol Cell Biol. 2013;33:2930–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sanchez-Arevalo LV, Doni M, Verrecchia A, Sanulli S, Faga G, Piontini A, et al. Dual regulation of Myc by Abl. Oncogene. 2013;32:5261–71.

    Article  Google Scholar 

  21. Helander S, Montecchio M, Pilstal R, Su Y, Kuruvilla J, Elven M, et al. Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity. Structure. 2015;23:2267–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wei Y, Redel C, Ahlner A, Lemak A, Johansson-Akhe I, Houliston S, et al. The MYC oncoprotein directly interacts with its chromatin cofactor PNUTS to recruit PP1 phosphatase. Nucleic Acids Res. 2022;50:3505–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dingar D, Tu WB, Resetca D, Lourenco C, Tamachi A, De Melo J, et al. MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability. Nat Commun. 2018;9:3502.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jiang J, Wang J, Yue M, Cai X, Wang T, Wu C, et al. Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis. Cancer Cell. 2020;37:200–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang XY, DeSalle LM, McMahon SB. Identification of novel targets of MYC whose transcription requires the essential MbII domain. Cell Cycle. 2006;5:238–41.

    Article  CAS  PubMed  Google Scholar 

  26. Nikiforov MA, Chandriani S, Park J, Kotenko I, Matheos D, Johnsson A, et al. TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins. Mol Cell Biol. 2002;22:5054–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell. 1998;94:363–74.

    Article  CAS  PubMed  Google Scholar 

  28. McMahon SB, Wood MA, Cole MD. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol. 2000;20:556–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Park J, Wood MA, Cole MD. BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol. 2002;22:1307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu F, Liao Z, Qin L, Zhang Z, Zhang Q, Han S, et al. Targeting VPS72 inhibits ACTL6A/MYC axis activity in HCC progression. Hepatology. 2023.

  31. Tu WB, Shiah YJ, Lourenco C, Mullen PJ, Dingar D, Redel C, et al. MYC Interacts with the G9a Histone Methyltransferase to Drive Transcriptional Repression and Tumorigenesis. Cancer Cell. 2018;34:579–95.

    Article  CAS  PubMed  Google Scholar 

  32. Kurland JF, Tansey WP. Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res. 2008;68:3624–9.

    Article  CAS  PubMed  Google Scholar 

  33. Pan J, Deng Q, Jiang C, Wang X, Niu T, Li H, et al. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene. 2015;34:3957–67.

    Article  CAS  PubMed  Google Scholar 

  34. Thomas LR, Foshage AM, Weissmiller AM, Tansey WP. The MYC-WDR5 Nexus and Cancer. Cancer Res. 2015;75:4012–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ansari MZ, Swaminathan R. Structure and dynamics at N- and C-terminal regions of intrinsically disordered human c-Myc PEST degron reveal a pH-induced transition. Proteins. 2020;88:889–909.

    Article  CAS  PubMed  Google Scholar 

  36. Rogers S, Wells R, Rechsteiner M. Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science. 1986;234:364–8.

    Article  CAS  PubMed  Google Scholar 

  37. Prakash S, Tian L, Ratliff KS, Lehotzky RE, Matouschek A. An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat Struct Mol Biol. 2004;11:830–7.

    Article  CAS  PubMed  Google Scholar 

  38. Gregory MA, Hann SR. c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt’s lymphoma cells. Mol Cell Biol. 2000;20:2423–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Popay TM, Wang J, Adams CM, Howard GC, Codreanu SG, Sherrod SD, et al. MYC regulates ribosome biogenesis and mitochondrial gene expression programs through its interaction with host cell factor-1. Elife. 2021;10:e60191.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dang CV, Lee WM. Identification of the human c-myc protein nuclear translocation signal. Mol Cell Biol. 1988;8:4048–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Conti E, Kuriyan J. Crystallographic analysis of the specific yet versatile recognition of distinct nuclear localization signals by karyopherin alpha. Structure. 2000;8:329–38.

    Article  CAS  PubMed  Google Scholar 

  42. Sammak S, Hamdani N, Gorrec F, Allen MD, Freund S, Bycroft M, et al. Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c-MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA. Biochem-Us. 2019;58:3144–54.

    Article  CAS  Google Scholar 

  43. Guo J, Li T, Schipper J, Nilson KA, Fordjour FK, Cooper JJ, et al. Sequence specificity incompletely defines the genome-wide occupancy of Myc. Genome Biol. 2014;15:482.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Prochownik EV, Wang H. Normal and neoplastic growth suppression by the extended Myc network. Cells. 2022;11:747.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Nascimento EM, Cox CL, MacArthur S, Hussain S, Trotter M, Blanco S, et al. The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis. Nat Cell Biol. 2011;13:1395–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schaub FX, Dhankani V, Berger AC, Trivedi M, Richardson AB, Shaw R, et al. Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas. Cell Syst. 2018;6:282–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Solhi R, Lotfinia M, Gramignoli R, Najimi M, Vosough M. Metabolic hallmarks of liver regeneration. Trends Endocrin. Met 2021;32:731–45.

    CAS  Google Scholar 

  48. Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastro Hepat. 2021;18:40–55.

    Article  Google Scholar 

  49. Sanders JA, Gruppuso PA. Nucleolar localization of hepatic c-Myc: a potential mechanism for c-Myc regulation. Biochim Biophys Acta. 2005;1743:141–50.

    Article  CAS  PubMed  Google Scholar 

  50. He C, Hu H, Braren R, Fong SY, Trumpp A, Carlson TR, et al. c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo. Development. 2008;135:2467–77.

    Article  CAS  PubMed  Google Scholar 

  51. Baena E, Gandarillas A, Vallespinos M, Zanet J, Bachs O, Redondo C, et al. c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver. Proc Natl Acad Sci USA. 2005;102:7286–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Qu A, Jiang C, Cai Y, Kim JH, Tanaka N, Ward JM, et al. Role of Myc in hepatocellular proliferation and hepatocarcinogenesis. J Hepatol. 2014;60:331–8.

    Article  CAS  PubMed  Google Scholar 

  53. Sanders JA, Schorl C, Patel A, Sedivy JM, Gruppuso PA. Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion. Bmc Physiol. 2012;12:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li F, Xiang Y, Potter J, Dinavahi R, Dang CV, Lee LA. Conditional deletion of c-myc does not impair liver regeneration. Cancer Res. 2006;66:5608–12.

    Article  CAS  PubMed  Google Scholar 

  55. Goto M, Ooshio T, Yamamoto M, Tanaka H, Fujii Y, Meng L, et al. High levels of Myc expression are required for the robust proliferation of hepatocytes, but not for the sustained weak proliferation. Bba-Mol Basis Dis. 2023;1869:166644.

    Article  CAS  Google Scholar 

  56. Kolodziejczyk AA, Federici S, Zmora N, Mohapatra G, Dori-Bachash M, Hornstein S, et al. Acute liver failure is regulated by MYC- and microbiome-dependent programs. Nat Med. 2020;26:1899–911.

    Article  CAS  PubMed  Google Scholar 

  57. Kotulkar M, Paine-Cabrera D, Abernathy S, Robarts DR, Parkes WS, Lin-Rahardja K, et al. Role of HNF4alpha-cMyc interaction in liver regeneration and recovery after acetaminophen-induced acute liver injury. Hepatology. 2023;78:1106–17.

    Article  PubMed  Google Scholar 

  58. Lin YH, Zeng Q, Jia Y, Wang Z, Li L, Hsieh MH, et al. In vivo screening identifies SPP2, a secreted factor that negatively regulates liver regeneration. Hepatology. 2023;78:1133–48.

    Article  PubMed  Google Scholar 

  59. Lee HM, Lidofsky SD, Taddei TH, Townshend-Bulson LJ. Attacking the public health crisis of hepatocellular carcinoma at its roots. Hepatology. 2023;77:1456–9.

    Article  PubMed  Google Scholar 

  60. Yan H, Yang Y, Zhang L, Tang G, Wang Y, Xue G, et al. Characterization of the genotype and integration patterns of hepatitis B virus in early- and late-onset hepatocellular carcinoma. Hepatology. 2015;61:1821–31.

    Article  CAS  PubMed  Google Scholar 

  61. Peneau 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.

    Article  CAS  PubMed  Google Scholar 

  62. Javanmard D, Najafi M, Babaei MR, Karbalaie NM, Esghaei M, Panahi M, et al. Investigation of CTNNB1 gene mutations and expression in hepatocellular carcinoma and cirrhosis in association with hepatitis B virus infection. Infect Agents Cancer. 2020;15:37.

    Article  CAS  Google Scholar 

  63. Balsano C, Avantaggiati ML, Natoli G, De Marzio E, Will H, Perricaudet M, et al. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Bioph Res Co. 1991;176:985–92.

    Article  CAS  Google Scholar 

  64. Lee S, Kim W, Ko C, Ryu WS. Hepatitis B virus X protein enhances Myc stability by inhibiting SCF(Skp2) ubiquitin E3 ligase-mediated Myc ubiquitination and contributes to oncogenesis. Oncogene. 2016;35:1857–67.

    Article  CAS  PubMed  Google Scholar 

  65. Shukla SK, Kumar V. Hepatitis B virus X protein and c-Myc cooperate in the upregulation of ribosome biogenesis and in cellular transformation. Febs J. 2012;279:3859–71.

    Article  CAS  PubMed  Google Scholar 

  66. Teng CF, Chang HY, Tsai HW, Hsieh WC, Kuo YH, Su IJ, et al. Liver regeneration accelerates hepatitis B virus-related tumorigenesis of hepatocellular carcinoma. Mol Oncol. 2018;12:1175–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Higgs MR, Lerat H, Pawlotsky JM. Hepatitis C virus-induced activation of beta-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events. Oncogene. 2013;32:4683–93.

    Article  CAS  PubMed  Google Scholar 

  68. Ma HC, Lin TW, Li H, Iguchi-Ariga SM, Ariga H, Chuang YL, et al. Hepatitis C virus ARFP/F protein interacts with cellular MM-1 protein and enhances the gene trans-activation activity of c-Myc. J Biomed Sci. 2008;15:417–25.

    Article  CAS  PubMed  Google Scholar 

  69. Xu H, Xiao P, Zhang F, Liu T, Gao Y. Epidemic characteristics of alcohol-related liver disease in Asia from 2000 to 2020: A systematic review and meta-analysis. Liver Int. 2022;42:1991–8.

    Article  PubMed  Google Scholar 

  70. Nevzorova YA, Cubero FJ, Hu W, Hao F, Haas U, Ramadori P, et al. Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease. J Hepatol. 2016;64:628–40.

    Article  CAS  PubMed  Google Scholar 

  71. Schlaeger C, Longerich T, Schiller C, Bewerunge P, Mehrabi A, Toedt G, et al. Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology. 2008;47:511–20.

    Article  CAS  PubMed  Google Scholar 

  72. Wong AM, Ding X, Wong AM, Xu M, Zhang L, Leung HH, et al. Unique molecular characteristics of NAFLD-associated liver cancer accentuate beta-catenin/TNFRSF19-mediated immune evasion. J Hepatol. 2022;77:410–23.

    Article  CAS  PubMed  Google Scholar 

  73. Ke X, Hu H, Peng Q, Ying H, Chu X. USP33 promotes nonalcoholic fatty acid disease-associated fibrosis in gerbils via the c-myc signaling. Biochem Bioph Res Co. 2023;669:68–76.

    Article  CAS  Google Scholar 

  74. Shin J, He M, Liu Y, Paredes S, Villanova L, Brown K, et al. SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep. 2013;5:654–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Nevzorova YA, Hu W, Cubero FJ, Haas U, Freimuth J, Tacke F, et al. Overexpression of c-myc in hepatocytes promotes activation of hepatic stellate cells and facilitates the onset of liver fibrosis. Biochim Biophys Acta. 2013;1832:1765–75.

    Article  CAS  PubMed  Google Scholar 

  76. Yeh MM, Shi X, Yang J, Li M, Fung KM, Daoud SS. Perturbation of Wnt/beta-catenin signaling and sexual dimorphism in non-alcoholic fatty liver disease. Hepatol Res. 2022;52:433–48.

    Article  CAS  PubMed  Google Scholar 

  77. Winkler M, Staniczek T, Kurschner SW, Schmid CD, Schonhaber H, Cordero J, et al. Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling. J Hepatol. 2021;74:380–93.

    Article  CAS  PubMed  Google Scholar 

  78. Qi Y, Qadir M, Hastreiter AA, Fock RA, Machi JF, Morales AA, et al. Endothelial c-Myc knockout enhances diet-induced liver inflammation and fibrosis. Faseb J. 2022;36:e22077.

    Article  CAS  PubMed  Google Scholar 

  79. Liu L, Zhou Y, Liu Z, Li J, Hu L, He L, et al. Osr1 Regulates Macrophage-mediated Liver Inflammation in Nonalcoholic Fatty Liver Disease Progression. Cell Mol Gastroenter. 2023;15:1117–33.

    CAS  Google Scholar 

  80. Luo Y, Yang S, Wu X, Takahashi S, Sun L, Cai J, et al. Intestinal MYC modulates obesity-related metabolic dysfunction. Nat Metab. 2021;3:923–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, Metabolism, and Cancer. Cancer Discov. 2015;5:1024–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kaposi-Novak P, Libbrecht L, Woo HG, Lee YH, Sears NC, Coulouarn C, et al. Central role of c-Myc during malignant conversion in human hepatocarcinogenesis. Cancer Res. 2009;69:2775–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology. 2015;149:1226–39.

    Article  CAS  PubMed  Google Scholar 

  84. Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017;169:1327–41.

  85. Jia D, Wei L, Guo W, Zha R, Bao M, Chen Z, et al. Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma. Hepatology. 2011;54:1227–36.

    Article  CAS  PubMed  Google Scholar 

  86. Wang K, Lim HY, Shi S, Lee J, Deng S, Xie T, et al. Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma. Hepatology. 2013;58:706–17.

    Article  PubMed  Google Scholar 

  87. D’Artista L, Moschopoulou AA, Barozzi I, Craig AJ, Seehawer M, Herrmann L, et al. MYC determines lineage commitment in KRAS-driven primary liver cancer development. J Hepatol. 2023;79:141–9.

    Article  PubMed  Google Scholar 

  88. Huang H, Wu L, Lu L, Zhang Z, Qiu B, Mo J, et al. Single-cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma. Hepatology. 2023;77:1911–28.

    Article  PubMed  Google Scholar 

  89. Eichenmuller M, Trippel F, Kreuder M, Beck A, Schwarzmayr T, Haberle B, et al. The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol. 2014;61:1312–20.

    Article  PubMed  Google Scholar 

  90. Fan L, Pan Q, Yang W, Koo SC, Tian C, Li L, et al. A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis. Hepatology. 2022;76:1275–90.

    Article  CAS  PubMed  Google Scholar 

  91. Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555:321–7.

    Article  PubMed  Google Scholar 

  92. Zhang Y, Solinas A, Cairo S, Evert M, Chen X, Calvisi DF. Molecular Mechanisms of Hepatoblastoma. Semin Liver Dis. 2021;41:28–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002;21:4863–71.

    Article  CAS  PubMed  Google Scholar 

  94. Comerford SA, Hinnant EA, Chen Y, Bansal H, Klapproth S, Rakheja D, et al. Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant beta-catenin. Jci Insight. 2016;1:e88549.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang H, Lu J, Edmunds LR, Kulkarni S, Dolezal J, Tao J, et al. Coordinated Activities of Multiple Myc-dependent and Myc-independent Biosynthetic Pathways in Hepatoblastoma. J Biol Chem. 2016;291:26241–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang H, Lu J, Mandel JA, Zhang W, Schwalbe M, Gorka J, et al. Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas. Cell Mol Gastroenter. 2021;12:199–228.

    CAS  Google Scholar 

  97. Chow EK, Fan LL, Chen X, Bishop JM. Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells. Hepatology. 2012;56:1331–41.

    Article  CAS  PubMed  Google Scholar 

  98. Xiang D, Cheng Z, Liu H, Wang X, Han T, Sun W, et al. Shp2 promotes liver cancer stem cell expansion by augmenting beta-catenin signaling and predicts chemotherapeutic response of patients. Hepatology. 2017;65:1566–80.

    Article  CAS  PubMed  Google Scholar 

  99. Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D, et al. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology. 2011;54:1031–42.

    Article  CAS  PubMed  Google Scholar 

  100. Huan HB, Yang DP, Wen XD, Chen XJ, Zhang L, Wu LL, et al. HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial-mesenchymal transition. J Exp Clin Canc Res. 2017;36:86.

    Article  Google Scholar 

  101. Claveria-Cabello A, Herranz JM, Latasa MU, Arechederra M, Uriarte I, Pineda-Lucena A, et al. Identification and experimental validation of druggable epigenetic targets in hepatoblastoma. J Hepatol. 2023;79:989–1005.

    Article  CAS  PubMed  Google Scholar 

  102. Cairo S, Armengol C, De Reynies A, Wei Y, Thomas E, Renard CA, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14:471–84.

    Article  CAS  PubMed  Google Scholar 

  103. Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S, et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004;431:1112–7.

    Article  CAS  PubMed  Google Scholar 

  104. Mendez-Lucas A, Li X, Hu J, Che L, Song X, Jia J, et al. Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be Sustained by Various PKM1/PKM2 Ratios and Pyruvate Kinase Activities. Cancer Res. 2017;77:4355–64.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wang D, Tian J, Yan Z, Yuan Q, Wu D, Liu X, et al. Mitochondrial fragmentation is crucial for c-Myc-driven hepatoblastoma-like liver tumors. Mol Ther. 2022;30:1645–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Chen WS, Liang Y, Zong M, Liu JJ, Kaneko K, Hanley KL, et al. Single-cell transcriptomics reveals opposing roles of Shp2 in Myc-driven liver tumor cells and microenvironment. Cell Rep. 2021;37:109974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang H, Song X, Liao H, Wang P, Zhang Y, Che L, et al. Overexpression of Mothers Against Decapentaplegic Homolog 7 Activates the Yes-Associated Protein/NOTCH Cascade and Promotes Liver Carcinogenesis in Mice and Humans. Hepatology. 2021;74:248–63.

    Article  CAS  PubMed  Google Scholar 

  108. Tang M, Zhao Y, Zhao J, Wei S, Liu M, Zheng N, et al. Liver cancer heterogeneity modeled by in situ genome editing of hepatocytes. Sci Adv. 2022;8:eabn5683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ruiz DGM, Bresnahan E, Molina-Sanchez P, Lindblad KE, Maier B, Sia D, et al. beta-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov. 2019;9:1124–41.

    Article  Google Scholar 

  110. Sun L, Wang Y, Cen J, Ma X, Cui L, Qiu Z, et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat Cell Biol. 2019;21:1015–26.

    Article  CAS  PubMed  Google Scholar 

  111. Jiang Z, Cheng L, Wu Z, Zhou L, Wang H, Hong Q, et al. Transforming primary human hepatocytes into hepatocellular carcinoma with genetically defined factors. Embo Rep. 2022;23:e54275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Seehawer M, Heinzmann F, D’Artista L, Harbig J, Roux PF, Hoenicke L, et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature. 2018;562:69–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Coppola JA, Cole MD. Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment. Nature. 1986;320:760–3.

    Article  CAS  PubMed  Google Scholar 

  114. Prochownik EV, Kukowska J. Deregulated expression of c-myc by murine erythroleukaemia cells prevents differentiation. Nature. 1986;322:848–50.

    Article  CAS  PubMed  Google Scholar 

  115. Leon J, Ferrandiz N, Acosta JC, Delgado MD. Inhibition of cell differentiation: a critical mechanism for MYC-mediated carcinogenesis? Cell Cycle. 2009;8:1148–57.

    Article  CAS  PubMed  Google Scholar 

  116. Schonfeld M, Averilla J, Gunewardena S, Weinman SA, Tikhanovich I. Male-Specific Activation of Lysine Demethylases 5B and 5C Mediates Alcohol-Induced Liver Injury and Hepatocyte Dedifferentiation. Hepatol Commun. 2022;6:1373–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sullivan DK, Deutzmann A, Yarbrough J, Krishnan MS, Gouw AM, Bellovin DI, et al. MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes. Oncogene. 2022;41:4960–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Watanabe K, Yamamoto M, Xin B, Ooshio T, Goto M, Fujii K, et al. Emergence of the Dedifferentiated Phenotype in Hepatocyte-Derived Tumors in Mice: Roles of Oncogene-Induced Epigenetic Alterations. Hepatol Commun. 2019;3:697–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang Y, Yan Q, Gong L, Xu H, Liu B, Fang X, et al. C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism. Oncogene. 2021;40:1147–61.

    Article  CAS  PubMed  Google Scholar 

  120. Liu J, Xu R, Mai SJ, Ma YS, Zhang MY, Cao PS, et al. LncRNA CSMD1-1 promotes the progression of Hepatocellular Carcinoma by activating MYC signaling. Theranostics. 2020;10:7527–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Koo JI, Lee HJ, Jung JH, Im E, Kim JH, Shin N, et al. The Pivotal Role of Long Noncoding RNA RAB5IF in the Proliferation of Hepatocellular Carcinoma Via LGR5 Mediated beta-Catenin and c-Myc Signaling. Biomolecules. 2019;9:718.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Zhang N, Chen X. A positive feedback loop involving the LINC00346/beta-catenin/MYC axis promotes hepatocellular carcinoma development. Cell Oncol. 2020;43:137–53.

    Article  Google Scholar 

  123. Zhou HZ, Li F, Cheng ST, Xu Y, Deng HJ, Gu DY, et al. DDX17-regulated alternative splicing that produced an oncogenic isoform of PXN-AS1 to promote HCC metastasis. Hepatology. 2022;75:847–65.

    Article  CAS  PubMed  Google Scholar 

  124. Yu M, Chen Z, Zhou Q, Zhang B, Huang J, Jin L, et al. PARG inhibition limits HCC progression and potentiates the efficacy of immune checkpoint therapy. J Hepatol. 2022;77:140–51.

    Article  CAS  PubMed  Google Scholar 

  125. Hu Z, Dong L, Li S, Li Z, Qiao Y, Li Y, et al. Splicing Regulator p54(nrb) /Non-POU Domain-Containing Octamer-Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box-Dependent Interacting Protein 1 in Hepatocellular Carcinoma. Hepatology. 2020;72:548–68.

    Article  CAS  PubMed  Google Scholar 

  126. Akita H, Marquardt JU, Durkin ME, Kitade M, Seo D, Conner EA, et al. MYC activates stem-like cell potential in hepatocarcinoma by a p53-dependent mechanism. Cancer Res. 2014;74:5903–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ma XL, Hu B, Tang WG, Xie SH, Ren N, Guo L, et al. CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma. J Hematol Oncol. 2020;13:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wu WR, Shi XD, Zhang FP, Zhu K, Zhang R, Yu XH, et al. Activation of the Notch1-c-myc-VCAM1 signalling axis initiates liver progenitor cell-driven hepatocarcinogenesis and pulmonary metastasis. Oncogene. 2022;41:2340–56.

    Article  CAS  PubMed  Google Scholar 

  129. Cairo S, Wang Y, de Reynies A, Duroure K, Dahan J, Redon MJ, et al. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. P Natl Acad Sci USA. 2010;107:20471–6.

    Article  CAS  Google Scholar 

  130. Zhang F, Hu K, Liu W, Quan B, Li M, Lu S, et al. Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment. Cell Mol Gastroenter. 2023;15:573–91.

    Google Scholar 

  131. Wang X, Zhang P, Deng K. MYC Promotes LDHA Expression through MicroRNA-122-5p to Potentiate Glycolysis in Hepatocellular Carcinoma. Anal Cell Pathol. 2022;2022:1435173.

    Article  Google Scholar 

  132. Yu Q, Dai W, Ji J, Wu L, Feng J, Li J, et al. Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c-myc/hexokinase 2 pathway. J Cell Mol Med. 2022;26:3031–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Fang J, Singh S, Cheng C, Natarajan S, Sheppard H, Abu-Zaid A, et al. Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma. Nat Commun. 2023;14:4003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Satriano L, Lewinska M, Rodrigues PM, Banales JM, Andersen JB. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastro Hepat. 2019;16:748–66.

    Article  CAS  Google Scholar 

  135. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69:7385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Bidkhori G, Benfeitas R, Klevstig M, Zhang C, Nielsen J, Uhlen M, et al. Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. Proc Natl Acad Sci USA. 2018;115:E11874–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res. 2012;18:5546–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Xia P, Zhang H, Lu H, Xu K, Jiang X, Jiang Y, et al. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression. Cancer Commun. 2023;43:338–64.

    Article  Google Scholar 

  139. Xu K, Ding J, Zhou L, Li D, Luo J, Wang W, et al. SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis. Cells. 2022;12:25.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Xie H, Tong G, Zhang Y, Liang S, Tang K, Yang Q. PGK1 Drives Hepatocellular Carcinoma Metastasis by Enhancing Metabolic Process. Int J Mol Sci. 2017;18:1630.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Yu L, Kim J, Jiang L, Feng B, Ying Y, Ji KY, et al. MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing. Nat Commun. 2020;11:708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wu Y, Wang Y, Yao H, Li H, Meng F, Li Q, et al. MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation. J Exp Clin Canc Res. 2022;41:337.

    Article  CAS  Google Scholar 

  143. Wei Y, Tang X, Ren Y, Yang Y, Song F, Fu J, et al. An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity. Signal Transduct Tar. 2021;6:421.

    Article  CAS  Google Scholar 

  144. Jiang J, Zheng Q, Zhu W, Chen X, Lu H, Chen D, et al. Alterations in glycolytic/cholesterogenic gene expression in hepatocellular carcinoma. Aging. 2020;12:10300–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen J, Ding C, Chen Y, Hu W, Yu C, Peng C, et al. ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway. Cancer Lett. 2021;502:154–65.

    Article  CAS  PubMed  Google Scholar 

  146. Zhao L, Su H, Liu X, Wang H, Feng Y, Wang Y, et al. mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell Biosci. 2022;12:183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Li X, Qian X, Peng LX, Jiang Y, Hawke DH, Zheng Y, et al. A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol. 2016;18:561–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Liu R, Li Y, Tian L, Shi H, Wang J, Liang Y, et al. Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating beta-catenin/c-Myc signaling in human hepatocellular carcinoma. Cancer Lett. 2019;443:34–46.

    Article  CAS  PubMed  Google Scholar 

  149. Wang KX, Du GH, Qin XM, Gao L. Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating beta-catenin/c-Myc signaling. Phytomedicine. 2021;93:153781.

    Article  CAS  PubMed  Google Scholar 

  150. Lee S, Byun JK, Kim NY, Jin J, Woo H, Choi YK, et al. Melatonin inhibits glycolysis in hepatocellular carcinoma cells by downregulating mitochondrial respiration and mTORC1 activity. Bmb Rep. 2022;55:459–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Liu N, Chang CW, Steer CJ, Wang XW, Song G. MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication Between Kupffer Cells and Regulatory T Cells. Gastroenterology. 2022;162:575–89.

    Article  CAS  PubMed  Google Scholar 

  152. Dhanasekaran R, Baylot V, Kim M, Kuruvilla S, Bellovin DI, Adeniji N, et al. MYC and Twist1 cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity. Elife. 2020;9:e50731.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Dhanasekaran R, Hansen AS, Park J, Lemaitre L, Lai I, Adeniji N, et al. MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages. Cancer Res. 2023;83:626–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. van Riggelen J, Muller J, Otto T, Beuger V, Yetil A, Choi PS, et al. The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance. Gene Dev. 2010;24:1281–94.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Reimann M, Lee S, Loddenkemper C, Dorr JR, Tabor V, Aichele P, et al. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 2010;17:262–72.

    Article  CAS  PubMed  Google Scholar 

  156. Liu N, Steer CJ, Song G. MicroRNA-206 enhances antitumor immunity by disrupting the communication between malignant hepatocytes and regulatory T cells in c-Myc mice. Hepatology. 2022;76:32–47.

    Article  CAS  PubMed  Google Scholar 

  157. Muthalagu N, Monteverde T, Raffo-Iraolagoitia X, Wiesheu R, Whyte D, Hedley A, et al. Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2020;10:872–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Luo Y, Gao Y, Liu W, Yang Y, Jiang J, Wang Y, et al. Myelocytomatosis-Protein Arginine N-Methyltransferase 5 Axis Defines the Tumorigenesis and Immune Response in Hepatocellular Carcinoma. Hepatology. 2021;74:1932–51.

    Article  CAS  PubMed  Google Scholar 

  159. Xu Y, Poggio M, Jin HY, Shi Z, Forester CM, Wang Y, et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat Med. 2019;25:301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Pai S, Bamodu OA, Lin YK, Lin CS, Chu PY, Chien MH, et al. CD47-SIRPalpha Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma. Cells. 2019;8:1658.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Kamijo H, Miyagaki T, Takahashi-Shishido N, Nakajima R, Oka T, Suga H, et al. Thrombospondin-1 promotes tumor progression in cutaneous T-cell lymphoma via CD47. Leukemia. 2020;34:845–56.

    Article  CAS  PubMed  Google Scholar 

  162. Yuen VW, Chiu DK, Law CT, Cheu JW, Chan CY, Wong BP, et al. Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses. J Hepatol. 2023;78:376–89.

    Article  CAS  PubMed  Google Scholar 

  163. Benson AB, D’Angelica MI, Abbott DE, Anaya DA, Anders R, Are C, et al. Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Ne. 2021;19:541–65.

    Article  Google Scholar 

  164. Hou Z, Liu J, Jin Z, Qiu G, Xie Q, Mi S, et al. Use of chemotherapy to treat hepatocellular carcinoma. Biosci Trends. 2022;16:31–45.

    Article  CAS  PubMed  Google Scholar 

  165. Zheng YH, Hu WJ, Chen BC, Grahn TH, Zhao YR, Bao HL, et al. BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver Int. 2016;36:1836–47.

    Article  CAS  PubMed  Google Scholar 

  166. Yin X, Tang B, Li JH, Wang Y, Zhang L, Xie XY, et al. ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway. J Exp Clin Canc Res. 2017;36:166.

    Article  Google Scholar 

  167. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.

    Article  CAS  PubMed  Google Scholar 

  168. Liu F, Dong X, Lv H, Xiu P, Li T, Wang F, et al. Targeting hypoxia-inducible factor-2alpha enhances sorafenib antitumor activity via beta-catenin/C-Myc-dependent pathways in hepatocellular carcinoma. Oncol Lett. 2015;10:778–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Lin YT, Lu HP, Chao CC. Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis. Biochem Pharm. 2015;93:110–24.

    Article  CAS  PubMed  Google Scholar 

  170. Huo Q, Ge C, Tian H, Sun J, Cui M, Li H, et al. Dysfunction of IKZF1/MYC/MDIG axis contributes to liver cancer progression through regulating H3K9me3/p21 activity. Cell Death Dis. 2017;8:e2766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wang JW, Ma L, Liang Y, Yang XJ, Wei S, Peng H, et al. RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1alpha-XBP1s pathway. Cell Death Discov. 2021;7:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Xia P, Zhang H, Xu K, Jiang X, Gao M, Wang G, et al. MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma. Cell Death Dis. 2021;12:691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ma L, Liu W, Xu A, Ji Q, Ma Y, Tai Y, et al. Activator of thyroid and retinoid receptor increases sorafenib resistance in hepatocellular carcinoma by facilitating the Warburg effect. Cancer Sci. 2020;111:2028–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Suk FM, Wu CY, Chiu WC, Chien CY, Chen TL, Liao YJ. HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells. Molecules. 2022;27:8015.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Loh JJ, Li TW, Zhou L, Wong TL, Liu X, Ma V, et al. FSTL1 Secreted by Activated Fibroblasts Promotes Hepatocellular Carcinoma Metastasis and Stemness. Cancer Res. 2021;81:5692–705.

    Article  CAS  PubMed  Google Scholar 

  176. Wang S, Zhou L, Ji N, Sun C, Sun L, Sun J, et al. Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression. Drug Resist Update. 2023;69:100976.

    Article  CAS  Google Scholar 

  177. Chiu DK, Yuen VW, Cheu JW, Wei LL, Ting V, Fehlings M, et al. Hepatocellular Carcinoma Cells Up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice. Gastroenterology. 2020;159:609–23.

    Article  CAS  PubMed  Google Scholar 

  178. Gao X, You J, Gong Y, Yuan M, Zhu H, Fang L, et al. WSB1 regulates c-Myc expression through beta-catenin signaling and forms a feedforward circuit. Acta Pharm Sin B. 2022;12:1225–39.

    Article  CAS  PubMed  Google Scholar 

  179. Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. beta-Catenin signaling in hepatocellular carcinoma. J Clin Invest. 2022;132:e154515.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Lin CH, Kuo JC, Li D, Koenig AB, Pan A, Yan P, et al. AZD5153, a Bivalent BRD4 Inhibitor, Suppresses Hepatocarcinogenesis by Altering BRD4 Chromosomal Landscape and Modulating the Transcriptome of HCC Cells. Front Cell Dev Biol. 2022;10:853652.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Tsang FH, Law CT, Tang TC, Cheng CL, Chin DW, Tam WV, et al. Aberrant Super-Enhancer Landscape in Human Hepatocellular Carcinoma. Hepatology. 2019;69:2502–17.

    Article  CAS  PubMed  Google Scholar 

  183. Wu H, Yang TY, Li Y, Ye WL, Liu F, He XS, et al. Tumor Necrosis Factor Receptor-Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c-Myc Gene Expression and Protein Stability. Hepatology. 2020;71:148–63.

    Article  CAS  PubMed  Google Scholar 

  184. Choi HI, An GY, Yoo E, Baek M, Chai JC, Binas B, et al. Targeting of noncoding RNAs encoded by a novel MYC enhancers inhibits the proliferation of human hepatic carcinoma cells in vitro. Sci Rep-Uk. 2022;12:855.

    Article  CAS  Google Scholar 

  185. Choi HI, An GY, Baek M, Yoo E, Chai JC, Lee YS, et al. BET inhibitor suppresses migration of human hepatocellular carcinoma by inhibiting SMARCA4. Sci Rep-Uk. 2021;11:11799.

    Article  CAS  Google Scholar 

  186. Li GQ, Guo WZ, Zhang Y, Seng JJ, Zhang HP, Ma XX, et al. Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget. 2016;7:2462–74.

    Article  PubMed  Google Scholar 

  187. Thng D, Toh TB, Pigini P, Hooi L, Dan YY, Chow PK, et al. Splice-switch oligonucleotide-based combinatorial platform prioritizes synthetic lethal targets CHK1 and BRD4 against MYC-driven hepatocellular carcinoma. Bioeng Transl Med. 2023;8:e10363.

    Article  CAS  PubMed  Google Scholar 

  188. Singh AR, Joshi S, Burgoyne AM, Sicklick JK, Ikeda S, Kono Y, et al. Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma. Mol Cancer Ther. 2016;15:2553–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Liu R, Gou D, Xiang J, Pan X, Gao Q, Zhou P, et al. O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis. Oncogene. 2021;40:6707–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Hou R, Li Y, Luo X, Zhang W, Yang H, Zhang Y, et al. ENKUR expression induced by chemically synthesized cinobufotalin suppresses malignant activities of hepatocellular carcinoma by modulating beta-catenin/c-Jun/MYH9/USP7/c-Myc axis. Int J Biol Sci. 2022;18:2553–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Zhang P, Sun H, Wen P, Wang Y, Cui Y, Wu J. circRNA circMED27 acts as a prognostic factor and mediator to promote lenvatinib resistance of hepatocellular carcinoma. Mol Ther-Nucl Acids. 2022;27:293–303.

    Article  Google Scholar 

  192. Sun X, Cai M, Wu L, Zhen X, Chen Y, Peng J, et al. Ubiquitin-specific protease 28 deubiquitinates TCF7L2 to govern the action of the Wnt signaling pathway in hepatic carcinoma. Cancer Sci. 2022;113:3463–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Sun W, Shen J, Liu J, Han K, Liang L, Gao Y. Gene Signature and Prognostic Value of Ubiquitin-Specific Proteases Members in Hepatocellular Carcinoma and Explored the Immunological Role of USP36. Front Biosci-Landmrk. 2022;27:190.

    Article  CAS  Google Scholar 

  194. Tu K, Yang W, Li C, Zheng X, Lu Z, Guo C, et al. Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma. Mol Cancer. 2014;13:110.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Bekes M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21:181–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol. 2020;13:50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Saraswat A, Vemana HP, Dukhande VV, Patel K. Galactose-decorated liver tumor-specific nanoliposomes incorporating selective BRD4-targeted PROTAC for hepatocellular carcinoma therapy. Heliyon. 2022;8:e8702.

    Article  Google Scholar 

  198. Zhang H, Li G, Zhang Y, Shi J, Yan B, Tang H, et al. Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells. Front Oncol. 2019;9:1471.

    Article  PubMed  Google Scholar 

  199. Saraswat A, Patki M, Fu Y, Barot S, Dukhande VV, Patel K. Nanoformulation of PROteolysis TArgeting Chimera targeting ‘undruggable’ c-Myc for the treatment of pancreatic cancer. Nanomed-Uk. 2020;15:1761–77.

    Article  CAS  Google Scholar 

  200. Shi C, Zhang H, Wang P, Wang K, Xu D, Wang H, et al. PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis. Cell Death Dis. 2019;10:815.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Fu Y, Saraswat A, Wei Z, Agrawal MY, Dukhande VV, Reznik SE, et al. Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma. Pharmaceutics. 2021;13:1005.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Li X, Zhang Z, Gao F, Ma Y, Wei D, Lu Z, et al. c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer. J Am Chem Soc. 2023;145:9334–42.

    Article  CAS  PubMed  Google Scholar 

  203. Zhang S, Hu Y, Wu Z, Zhou X, Wu T, Li P, et al. Deficiency of Carbamoyl Phosphate Synthetase 1 Engenders Radioresistance in Hepatocellular Carcinoma via Deubiquitinating c-Myc. Int J Radiat Oncol. 2023;115:1244–56.

    Article  Google Scholar 

  204. Lin CP, Liu JD, Chow JM, Liu CR, Liu HE. Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cells. Anti-Cancer Drug. 2007;18:161–70.

    Article  CAS  Google Scholar 

  205. Sequera C, Grattarola M, Holczbauer A, Dono R, Pizzimenti S, Barrera G, et al. MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities. Cell Death Dis. 2022;13:994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Soucek L, Helmer-Citterich M, Sacco A, Jucker R, Cesareni G, Nasi S. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene. 1998;17:2463–72.

    Article  CAS  PubMed  Google Scholar 

  207. Soucek L, Jucker R, Panacchia L, Ricordy R, Tato F, Nasi S. Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 2002;62:3507–10.

    CAS  PubMed  Google Scholar 

  208. Beaulieu ME, Jauset T, Masso-Valles D, Martinez-Martin S, Rahl P, Maltais L, et al. Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy. Sci Transl Med. 2019;11:eaar5012.

    Article  PubMed  PubMed Central  Google Scholar 

  209. Wang E, Sorolla A, Cunningham PT, Bogdawa HM, Beck S, Golden E, et al. Tumor penetrating peptides inhibiting MYC as a potent targeted therapeutic strategy for triple-negative breast cancers. Oncogene. 2019;38:140–50.

    Article  CAS  PubMed  Google Scholar 

  210. Garralda E, Moreno V, Alonso G, Corral E, Hernandez-Guerrero T, Ramon J, et al. 7 Oral - Dose escalation study of OMO-103, a first in class Pan-MYC-Inhibitor in patients (pts) with advanced solid tumors. Eur J Cancer. 2022;174:S5–6.

    Article  Google Scholar 

  211. Kwan SY, Sheel A, Song CQ, Zhang XO, Jiang T, Dang H, et al. Depletion of TRRAP Induces p53-Independent Senescence in Liver Cancer by Down-Regulating Mitotic Genes. Hepatology. 2020;71:275–90.

    Article  CAS  PubMed  Google Scholar 

  212. Thng D, Hooi L, Toh C, Lim JJ, Rajagopalan D, Syariff I, et al. Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer. Mol Oncol. 2023.

  213. Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, et al. Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell. 2015;58:440–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Thomas LR, Adams CM, Wang J, Weissmiller AM, Creighton J, Lorey SL, et al. Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance. P Natl Acad Sci USA. 2019;116:25260–8.

    Article  CAS  Google Scholar 

  215. Gao W, Jia Z, Tian Y, Yang P, Sun H, Wang C, et al. HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein. Hepatology. 2020;71:1678–95.

    Article  CAS  PubMed  Google Scholar 

  216. Chen T, Li K, Liu Z, Liu J, Wang Y, Sun R, et al. WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1alpha accumulation in Myc-dependent and independent pathways. Mol Ther. 2021;29:2134–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Lu K, Tao H, Si X, Chen Q. The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer. Front Oncol. 2018;8:502.

    Article  PubMed  PubMed Central  Google Scholar 

  218. Huang CH, Lujambio A, Zuber J, Tschaharganeh DF, Doran MG, Evans MJ, et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Gene Dev. 2014;28:1800–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Xie G, Zhu A, Gu X. Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition. Cancers (Basel). 2022;14:1714.

    Article  PubMed  Google Scholar 

  220. Fan W, Yang H, Liu T, Wang J, Li TW, Mavila N, et al. Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells. Hepatology. 2017;65:1249–66.

    Article  CAS  PubMed  Google Scholar 

  221. Chen D, Zou J, Zhao Z, Tang X, Deng Z, Jia J, et al. TXNDC9 promotes hepatocellular carcinoma progression by positive regulation of MYC-mediated transcriptional network. Cell Death Dis. 2018;9:1110.

    Article  PubMed  PubMed Central  Google Scholar 

  222. Liao P, Zeng SX, Zhou X, Chen T, Zhou F, Cao B, et al. Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding. Mol Cell. 2017;68:1134–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Wang H, Zhang S, Zhang Y, Jia J, Wang J, Liu X, et al. TAZ is indispensable for c-MYC-induced hepatocarcinogenesis. J Hepatol. 2022;76:123–34.

    Article  CAS  PubMed  Google Scholar 

  224. Bisso A, Filipuzzi M, Gamarra FG, Brumana G, Biagioni F, Doni M, et al. Cooperation Between MYC and beta-Catenin in Liver Tumorigenesis Requires Yap/Taz. Hepatology. 2020;72:1430–43.

    Article  CAS  PubMed  Google Scholar 

  225. Xu Z, Xu M, Liu P, Zhang S, Shang R, Qiao Y, et al. The mTORC2-Akt1 Cascade Is Crucial for c-Myc to Promote Hepatocarcinogenesis in Mice and Humans. Hepatology. 2019;70:1600–13.

    Article  CAS  PubMed  Google Scholar 

  226. O’Donnell KA, Keng VW, York B, Reineke EL, Seo D, Fan D, et al. A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer. Proc Natl Acad Sci USA. 2012;109:E1377–86.

    Article  PubMed  PubMed Central  Google Scholar 

  227. Suresh S, Durakoglugil D, Zhou X, Zhu B, Comerford SA, Xing C, et al. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer. Plos Genet. 2017;13:e1006650.

    Article  PubMed  PubMed Central  Google Scholar 

  228. Bollard J, Miguela V, Ruiz DGM, Venkatesh A, Bian CB, Roberto MP, et al. Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut. 2017;66:1286–96.

    Article  CAS  PubMed  Google Scholar 

  229. Sheng J, Kohno S, Okada N, Okahashi N, Teranishi K, Matsuda F, et al. Treatment of Retinoblastoma 1-Intact Hepatocellular Carcinoma With Cyclin-Dependent Kinase 4/6 Inhibitor Combination Therapy. Hepatology. 2021;74:1971–93.

    Article  CAS  PubMed  Google Scholar 

  230. Ryan CJ, Mehta I, Kebabci N, Adams DJ. Targeting synthetic lethal paralogs in cancer. Trends Cancer. 2023;9:397–409.

    Article  CAS  PubMed  Google Scholar 

  231. Thng D, Toh TB, Chow EK. Capitalizing on Synthetic Lethality of MYC to Treat Cancer in the Digital Age. Trends Pharm Sci. 2021;42:166–82.

    Article  CAS  PubMed  Google Scholar 

  232. Liu X, Song X, Zhang J, Xu Z, Che L, Qiao Y, et al. Focal adhesion kinase activation limits efficacy of Dasatinib in c-Myc driven hepatocellular carcinoma. Cancer Med-USA. 2018;7:6170–81.

    Article  CAS  Google Scholar 

  233. He DD, Shang XY, Wang N, Wang GX, He KY, Wang L, et al. BRD4 inhibition induces synthetic lethality in ARID2-deficient hepatocellular carcinoma by increasing DNA damage. Oncogene 2022;41:1397–409.

    Article  CAS  PubMed  Google Scholar 

  234. Kong D, Jiang Y, Miao X, Wu Z, Liu H, Gong W. Tadalafil enhances the therapeutic efficacy of BET inhibitors in hepatocellular carcinoma through activating Hippo pathway. Bba-Mol Basis Dis. 2021;1867:166267.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was funded National Natural Science Foundation of China (82172976, 81502530, 82103597).

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Authors and Affiliations

  1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Furong Liu, Zhibin Liao & Zhanguo Zhang

  2. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China

    Furong Liu, Zhibin Liao & Zhanguo Zhang

  3. Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China

    Furong Liu, Zhibin Liao & Zhanguo Zhang

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  1. Furong Liu
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ZZ and FL conceived this idea and outline the overall framework of this review. ZL provided the advices of this study. FL prepared the manuscript and the figures. All authors read and approved the final manuscript.

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Correspondence to Zhanguo Zhang.

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Liu, F., Liao, Z. & Zhang, Z. MYC in liver cancer: mechanisms and targeted therapy opportunities. Oncogene 42, 3303–3318 (2023). https://doi.org/10.1038/s41388-023-02861-w

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  • DOI: https://doi.org/10.1038/s41388-023-02861-w

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