BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair

  • Yuna Kim (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Baeki E. Kang (Department of Physiology, Sungkyunkwan University School of Medicine) ;
  • Karim Gariani (Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Geneva University Hospitals) ;
  • Joanna Gariani (Department of Radiology, Hirslanden Grangettes Clinic) ;
  • Junguee Lee (Department of Pathology, Konyang University) ;
  • Hyun-Jin Kim (Department of Physiology, Sungkyunkwan University School of Medicine) ;
  • Chang-Woo Lee (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Kristina Schoonjans (Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne) ;
  • Johan Auwerx (Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne) ;
  • Dongryeol Ryu (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine)
  • Received : 2023.10.09
  • Accepted : 2023.12.07
  • Published : 2024.02.29
Download PDF
⟨ Previous Next ⟩

Abstract

The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor.

Keywords

Acknowledgement

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2021R1A6A 3A13044725 to Y.K.; 2020R1A2C2010964, 2022K2A9A1A06 091879, 2023R1A2C3006220, RS-2023-00283539, and RS-2023-00261370 to D.R.). D.R. was supported by a "GIST Research Institute (GRI) IIBR" grant funded by the GIST in 2023.

References

  1. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71, 209-249  https://doi.org/10.3322/caac.21660
  2. Buitrago-Molina LE, Marhenke S, Longerich T et al (2013) The degree of liver injury determines the role of p21 in liver regeneration and hepatocarcinogenesis in mice. Hepatology 58, 1143-1152  https://doi.org/10.1002/hep.26412
  3. Fortini P, Ferretti C and Dogliotti E (2013) The response to DNA damage during differentiation: pathways and consequences. Mutat Res 743-744, 160-168  https://doi.org/10.1016/j.mrfmmm.2013.03.004
  4. Lee YH, Kuo CY, Stark JM, Shih HM and Ann DK (2013) HP1 promotes tumor suppressor BRCA1 functions during the DNA damage response. Nucleic Acids Res 41, 5784-5798  https://doi.org/10.1093/nar/gkt231
  5. Ogara MF, Sirkin PF, Carcagno AL et al (2013) Chromatin relaxation-mediated induction of p19INK4d increases the ability of cells to repair damaged DNA. PLoS One 8, e61143 
  6. Chalkiadaki A and Guarente L (2015) The multifaceted functions of sirtuins in cancer. Nat Rev Cancer 15, 608-624  https://doi.org/10.1038/nrc3985
  7. Cha YI and Kim HS (2013) Emerging role of sirtuins on tumorigenesis: possible link between aging and cancer. BMB Rep 46, 429-438  https://doi.org/10.5483/BMBRep.2013.46.9.180
  8. Bao X, Liu Z, Zhang W et al (2019) Glutarylation of histone H4 lysine 91 regulates chromatin dynamics. Mol Cell 76, 660-675 e669 
  9. Li L, Shi L, Yang S et al (2016) SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat Commun 7, 12235 
  10. Guo X, Yanna, Ma X et al (2011) A meta-analysis of array-CGH studies implicates antiviral immunity pathways in the development of hepatocellular carcinoma. PLoS One 6, e28404 
  11. Kim JK, Noh JH, Jung KH et al (2013) Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 57, 1055-1067  https://doi.org/10.1002/hep.26101
  12. Vesselinovitch SD, Koka M, Mihailovich N and Rao KV (1984) Carcinogenicity of diethylnitrosamine in newborn, infant, and adult mice. J Cancer Res Clin Oncol 108, 60-65  https://doi.org/10.1007/BF00390974
  13. Singer JB, Hill AE, Burrage LC et al (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304, 445-448  https://doi.org/10.1126/science.1093139
  14. Tsai YC, Greco TM, Boonmee A, Miteva Y and Cristea IM (2012) Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Mol Cell Proteomics 11, 60-76  https://doi.org/10.1074/mcp.A111.015156
  15. Onn L, Portillo M, Ilic S et al (2020) SIRT6 is a DNA double-strand break sensor. Elife 9, e51636 
  16. Shin J, He M, Liu Y et al (2013) SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep 5, 654-665  https://doi.org/10.1016/j.celrep.2013.10.007
  17. Ryu D, Jo YS, Lo Sasso G et al (2014) A SIRT7-dependent acetylation switch of GABPbeta1 controls mitochondrial function. Cell Metab 20, 856-869  https://doi.org/10.1016/j.cmet.2014.08.001
  18. Estes C, Razavi H, Loomba R, Younossi Z and Sanyal AJ (2018) Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123-133  https://doi.org/10.1002/hep.29466
  19. Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674  https://doi.org/10.1016/j.cell.2011.02.013
  20. Jackson SP and Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461, 1071-1078  https://doi.org/10.1038/nature08467
  21. Chung YL and Wu ML (2013) Promyelocytic leukaemia protein links DNA damage response and repair to hepatitis B virus-related hepatocarcinogenesis. J Pathol 230, 377-387  https://doi.org/10.1002/path.4195
  22. Bayram S, Akkiz H, Bekar A, Akgollu E and Yildirim S (2012) The significance of Exonuclease 1 K589E polymorphism on hepatocellular carcinoma susceptibility in the Turkish population: a case-control study. Mol Biol Rep 39, 5943-5951  https://doi.org/10.1007/s11033-011-1406-x
  23. Hsu CM, Yang MD, Chang WS et al (2013) The contribution of XRCC6/Ku70 to hepatocellular carcinoma in Taiwan. Anticancer Res 33, 529-535 
  24. Lees-Miller SP and Meek K (2003) Repair of DNA double strand breaks by non-homologous end joining. Biochimie 85, 1161-1173  https://doi.org/10.1016/j.biochi.2003.10.011
  25. Lieber MR (2008) The mechanism of human nonhomologous DNA end joining. J Biol Chem 283, 1-5  https://doi.org/10.1074/jbc.R700039200
  26. Thompson LH and Schild D (2001) Homologous recombinational repair of DNA ensures mammalian chromosome stability. Mutat Res 477, 131-153  https://doi.org/10.1016/S0027-5107(01)00115-4
  27. Teoh NC, Dan YY, Swisshelm K et al (2008) Defective DNA strand break repair causes chromosomal instability and accelerates liver carcinogenesis in mice. Hepatology 47, 2078-2088  https://doi.org/10.1002/hep.22194
  28. Vazquez BN, Thackray JK, Simonet NG et al (2016) SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair. EMBO J 35, 1488-1503  https://doi.org/10.15252/embj.201593499
  29. Kiran S, Oddi V and Ramakrishna G (2015) Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response. Exp Cell Res 331, 123-141  https://doi.org/10.1016/j.yexcr.2014.11.001
  30. Jeggo PA, Pearl LH and Carr AM (2016) DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer 16, 35-42  https://doi.org/10.1038/nrc.2015.4
  31. Nakamura AJ, Rao VA, Pommier Y and Bonner WM (2010) The complexity of phosphorylated H2AX foci formation and DNA repair assembly at DNA double-strand breaks. Cell Cycle 9, 389-397  https://doi.org/10.4161/cc.9.2.10475
  32. Wang HL, Lu RQ, Xie SH et al (2015) SIRT7 exhibits oncogenic potential in human ovarian cancer cells. Asian Pac J Cancer Prec 16, 3573-3577  https://doi.org/10.7314/APJCP.2015.16.8.3573
  33. Kim JK, Noh JH, Jung KH et al (2013) Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 57, 1055-1067  https://doi.org/10.1002/hep.26101
  34. Zhao J, Wozniak A, Adams A et al (2019) SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway. J Exp Clin Cancer Res 38, 252 
  35. Zhao J, Wozniak A, Adams A et al (2019) SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway. J Exp Clin Cancer Res 38, 252 
  36. Seligson DB, Horvath S, McBrian MA et al (2009) Global levels of histone modifications predict prognosis in different cancers. Am J Pathol 174, 1619-1628  https://doi.org/10.2353/ajpath.2009.080874
  37. Kim DH, Kim MJ, Kim NY et al (2022) DN200434, an orally available inverse agonist of estrogen-related receptor γ, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma. BMB Rep 55, 547-552  https://doi.org/10.5483/BMBRep.2022.55.11.089
  38. Moon B, Park M, Cho SH et al (2022) Synergistic antitumor activity of sorafenib and MG149 in hepatocellular carcinoma cells. BMB Rep 55, 506-511  https://doi.org/10.5483/BMBRep.2022.55.10.037
  39. Lee S, Byun JK, Kim NY et al (2022) Melatonin inhibits glycolysis in hepatocellular carcinoma cells by downregulating mitochondrial respiration and mTORC1 activity. BMB Rep 55, 459-464  https://doi.org/10.5483/BMBRep.2022.55.9.177
  40. Schulien I and Hasselblatt P (2021) Diethylnitrosamine-induced liver tumorigenesis in mice. Methods Cell Biol 163, 137-152  https://doi.org/10.1016/bs.mcb.2020.08.006
  41. Shirakami Y, Gottesman ME and Blaner WS (2012) Diethylnitrosamine-induced hepatocarcinogenesis is suppressed in lecithin: retinol acyltransferase-deficient mice primarily through retinoid actions immediately after carcinogen administration. Carcinogenesis 33, 268-274  https://doi.org/10.1093/carcin/bgr275
  42. Yoon YS, Ryu D, Lee MW, Hong S and Koo SH (2009) Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis. Exp Mol Med 41, 577-583  https://doi.org/10.3858/emm.2009.41.8.063
  43. Yamamoto H, Williams EG, Mouchiroud L et al (2011) NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147, 827-839  https://doi.org/10.1016/j.cell.2011.10.017
  44. Kim J, Lee H, Jin EJ et al (2022) A microfluidic device to fabricate one-step cell bead-laden hydrogel struts for tissue engineering. Small 18, e2106487 
  45. Kim J, Jo Y, Cho D and Ryu D (2022) L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans. Nat Commun 13, 6554