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Yang, Suk‐,Jin,Park, Young Soo,Cho, Jung Hee,Moon, Byul,An, Hyun‐,Jung,Lee, Ju Yeon,Xie, Zhi,Wang, Yuli,Pocalyko, David,Lee, Dong Chul,Sohn, Hyun Ahm,Kang, Minho,Kim, Jin Young,Kim, Eunhee EMBO 2017 The EMBO journal Vol.36 No.8
<P>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 alpha. 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 alpha downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1 alpha stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1 alpha 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 alpha stability.</P>