Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1{alpha} protein stability

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.

Source: EMBO Journal - April 13, 2017 Category: Molecular Biology Authors: Yang, S.-J., Park, Y. S., Cho, J. H., Moon, B., An, H.-J., Lee, J. Y., Xie, Z., Wang, Y., Pocalyko, D., Lee, D. C., Sohn, H. A., Kang, M., Kim, J. Y., Kim, E., Park, K. C., Kim, J.-A., Yeom, Y. I. Tags: Cancer, Metabolism, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research