Regulation of Hypoxia Responses by Flavin Adenine Dinucleotide-dependent Modulation of HIF-1α Protein Stability

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2017 Mar 11

PMID 28279976

Citations 30

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

Affiliations

Soon will be listed here.

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.

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