The Study Of HIF1a On Lipid Metabolism And Autophagy In Prostate Cancer

Objective Prostate cancer has become one of the most common cancers in men worldwide. According to the estimation from the American Cancer Society, about 1 in 7 males will be diagnosed with prostate cancer, during the lifetime. And hypoxia is an important marker in cancer. Overexpression of HIF1a has a significant correlation with progression and castration resistance in prostate caner. Moreover, in recent studies, upregulation of lipid metabolism and disregulation of autophagy has been found to promote tumorigenesis. Our research was to investigate the effects and mechanisms of HIFla on lipid metabolism and autophagy in prostate cancer cells. Methods The expression of HIF1a and lipogenic genes were compared in different prostate cancer cell lines by Real Time-Polymerase Chain Reaction (RT-PCR) and western blot. Then the expression of lipogenic genes in prostate cancer cells under hypoxic environment or transfected with HIF1a-mutant plasmid was analyzed. In addition, luciferase assay and ChIP assay were used to determined the underlying molecular mechanisms. On the other hand, we analyze the autophagy-related genes expression in hypoxic environments by Real Time-Polymerase Chain Reaction (RT-PCR) and western blot. Then to investigate the underlying molercular mechanism by luciferase assay and ChIP assay. Results HIF1a was elevated in a prostate mouse model TRAMP. There is some correlation between HIF1a and lipogenic genes. Hypoxic environment and overexpression of HIFla could increase the level of lipogenic genes. HIF1a could bind to the promoter of SREBP-lc and regulate its transcription. Compared to negative control (1.000±0.095,1.000±0.042), HDF1a could significant increase the mRNA (2.992±0.159) and protein (2.349±0.114) levels of SREBP-lc. HIF1a overexpression in prostate cancer xenografts elevated SREBP-1c, FASN and ACC1 protein expression, and increased tumor size. On the other hand, in prostate cancer cells, the level of autophagy was elevated in hypoxia condition, the RNA and protein expression of autophagy-related genes were increased. Futhermore, HIFla could activate the expression of ATG5, a pivotal regulator of autophagy on transcriptional level.Conclusion In hypoxic environment, HIF1a could promote de novo ligogenesis through promote the transcription of SREBP-1c in prostate cacner cells. And HIF1a could elevated the level of autophagy through increase ATG5 expression on the transcriptional level.