Regulation of hypoxia responses by flavin adenine dinucleotide‐dependent modulation of HIF ‐1α 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 ( LSD 1) upregulates hypoxia responses by demethylating RACK 1 protein, a component of hypoxia‐inducible factor ( HIF ) ubiquitination machinery, and consequently suppressing the oxygen‐independent degradation of HIF ‐1α. This ability of LSD 1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide ( FAD ), a metabolic cofactor of LSD 1, causing HIF ‐1α downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF ‐1α stability, indicating a rate‐limiting role for FAD in LSD 1‐mediated HIF ‐1α regulation. Transcriptomic analyses of patient tissues show that the HIF ‐1 signature is highly correlated with the expression of LSD 1 target genes as well as the enzymes of FAD biosynthetic pathway in triple‐negative breast cancers, reflecting the significance of FAD ‐dependent LSD 1 activity in cancer progression. Together, our findings provide a new insight into HIF ‐mediated hypoxia response regulation by coupling the FAD dependence of LSD 1 activity to the regulation of HIF ‐1α stability. image Lysine‐specific demethylase 1 ( LSD 1) promotes survival of cancer cells by demethylating the ubiquitin ligase component RACK 1 and inhibiting HIF ‐1α degradation. During prolonged hypoxia, diminished biosynthesis of the metabolic LSD 1 cofactor flavin adenine dinucleotide ( FAD ) unleashes RACK 1 and decreases HIF ‐1 protein levels. LSD1 is required for accumulation of HIF‐1 protein, upregulation of glycolysis, and survival in cancer cells under hypoxia. LSD1‐mediated RACK1 demethylation decreases its binding to HIF‐1α, suppressing oxygen‐independent HIF‐1α protein turnover. Lower FAD levels during prolonged hypoxia attenuate LSD1‐mediated RACK1 demethylation, causing HIF‐1α degradation. A HIF‐1 gene expression signature in triple‐negative breast cancer patients correlates with enzymatic activity of LSD1 and expression of FAD biosynthetic enzymes.