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Title 

Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1α protein stability

 

FAD 의존적인 HIF-1a 단백질 안정성 제어를 통한 저산소반응 조절 기전

Authors 

Suk Jin YangYoung Soo ParkJung Hee ChoByul MoonHyun Jung AhnJ Y LeeZ XieY WangD PocalykoDong Chul LeeHyun Ahm SohnMinho KangJ Y KimE KimKyung Chan ParkJung Ae KimYoung Il Yeom

Publisher 

Nature Publishing Group

Issue Date 

2012

Citation 

EMBO Journal

Keywords 

cancerFAD biosynthesisHIF-1hypoxiaLSD1

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.

ISSN 

0261-4191

Link 

http://dx.doi.org/10.15252/embj.201694408

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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