SirT1 confers hypoxia-induced radioresistance via the modulationof 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.