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‐1α. 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‐1α downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF‐1α stability, indicating a rate‐limiting role for FAD in LSD1‐mediated HIF‐1α 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‐1α stability.
Lysine‐specific demethylase 1 (LSD1) promotes survival of cancer cells by demethylating the ubiquitin ligase component RACK1 and inhibiting HIF‐1α degradation. During prolonged hypoxia, diminished biosynthesis of the metabolic LSD1 cofactor flavin adenine dinucleotide (FAD) unleashes RACK1 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.
The EMBO Journal (2017) 36: 1011–1028
- Received March 23, 2016.
- Revision received January 24, 2017.
- Accepted January 26, 2017.
- © 2017 The Authors
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