title: SirT1 regulates radiosensitivity of hepatoma cells differently under normoxic and hypoxic conditions.
abstract: Intratumoral hypoxic cells are more resistant to radiotherapy due to a reduction in lifespan of DNA-damaging free radicals and augmentation of post-irradiation molecular restoration. SirT1, a member of the mammalian sirtuin family, deacetylates various transcription factors to trigger cell defense and survival in response to stresses and DNA damage. In this study, we provide new evidence indicating that overexpression of SirT1 in hepatoma HepG2 cells allowed the cells to become much more resistant to irradiation under hypoxia than under normoxia. When SirT1 was knocked down in both HepG2 and SK-Hep-1 cells, the radiosensitivity was increased, especially under hypoxia. But this enhanced radiosensitivity in SirT1-deficient cells was extensively decreased by infecting cells with c-Myc siRNA. Furthermore, the expression of c-Myc protein and its acetylation were increased in the SirT1 knockdown cells and these increments under hypoxic conditions were much more notable than under normoxia. In addition, c-Myc interference significantly suppressed phosphorylated p53 protein expression after irradiation, especially under hypoxic conditions. The current findings indicate that SirT1 confers a higher radioresistance in hypoxic cells than in normoxic cells due to the decreased levels of c-Myc protein and its acetylation, and that a c-Myc-dependent radiation-induced phosphorylated p53 may be involved. SirT1 could serve as a novel target of radiation damage and thus as a potential strategy to advance the efficiency of radiotherapy in hepatoma entities.
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Xie
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuang
authors.initials: S
authors.lastname: Ye
authors.forename: Mingyuan
authors.initials: M
authors.lastname: He
authors.forename: Ruiping
authors.initials: R
authors.lastname: Ren
authors.forename: Dexiao
authors.initials: D
authors.lastname: Yuan
authors.forename: Chunlin
authors.initials: C
authors.lastname: Shao
mesh_terms: D000107:Acetylation / Q000528:radiation effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000528:radiation effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1