SirT1 confers hypoxia-induced radioresistance via the modulation of c-Myc stabilization on hepatoma cells.
Intratumoral hypoxia is an important contributory factor to tumor cell resistance to radiotherapy. SirT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent histone/protein deacetylase, has been linked to the decrease of radiation-induced DNA damage and seems to be critical for cancer therapy. The purpose of this study was to investigate the role of SirT1 in hypoxia-induced radiation response on hepatoma cells. It was found that the administration with resveratrol, a putative SirT1 activator, enhanced the resistance of HepG2 cells against radiation-induced DNA damage of MN formation under hypoxia condition; while nicotinamide, a well-known SirT1 inhibitor, sensitized this radiation damage. Nevertheless, pretreatment of cells with 10058-F4, a specific inhibitor of c-Myc, almost eliminated the nicotinamide-induced radiosensitive effect. Further studies revealed that resveratrol inhibited c-Myc protein accumulation via up-regulation of SirT1 expression and deacetylase activity, and this loss of c-Myc protein was abolished by inhibiting its degradation in the presence of MG132, a potent inhibitor of proteasome. In contrast, nicotinamide attenuated c-Myc protein degradation induced by radiation under hypoxia through inhibition of SirT1 deacetylase activity. Our findings suggest that SirT1 could serve as a novel potent target of radiation-induced DNA damage and thus as a potential strategy to advance the efficiency of radiation therapy in hepatoma entities.
Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China.
Yuexia
Y
Xie
Jianghong
J
Zhang
Yanwu
Y
Xu
Chunlin
C
Shao
D000107:Acetylation / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D005720:Gamma Rays / Q000009:adverse effects; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D015162:Micronucleus Tests; D009363:Neoplasm Proteins / Q000502:physiology*; D009536:Niacinamide / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011836:Radiation Tolerance / Q000187:drug effects*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D013267:Stilbenes; D025801:Ubiquitin; D009536:Niacinamide; D046988:Proteasome Endopeptidase Complex; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol