Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1? protein stability.

ABSTRACT: Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine-specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1?. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF-1? downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1? stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1? regulation. Transcriptomic analyses of patient tissues show that the HIF-1 signature is highly correlated with the expression of LSD1 target genes as well as the enzymes of FAD biosynthetic pathway in triple-negative breast cancers, reflecting the significance of FAD-dependent LSD1 activity in cancer progression. Together, our findings provide a new insight into HIF-mediated hypoxia response regulation by coupling the FAD dependence of LSD1 activity to the regulation of HIF-1? stability.

SUBMITTER: Yang SJ 

PROVIDER: S-EPMC5391145 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature