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 (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.

• Authors: Suk-Jin Yang, Young Soo Park, Jung Hee Cho, Byul Moon, Hyun-Jung An, Ju Yeon Lee, Zhi Xie, Yuli Wang, David Pocalyko, Dong Chul Lee, Hyun Ahm Sohn, Minho Kang, Jin Young Kim, Eunhee Kim, Kyung Chan Park, Jung-Ae Kim, Young Il Yeom
• Journal: The EMBO journal (EMBO J) Vol. 36 Issue 8 Pg. 1011-1028 (04 13 2017) ISSN: 1460-2075 [Electronic] England
• PMID: 28279976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Flavin-Adenine Dinucleotide
• Histone Demethylases
• KDM1A protein, human

Topics

• Cell Hypoxia
• Flavin-Adenine Dinucleotide (genetics, metabolism)
• Gene Expression Regulation
• Histone Demethylases (genetics, metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism, pathology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Protein Stability
• Ubiquitination