Journal
EMBO JOURNAL
Volume 36, Issue 8, Pages 1011-1028Publisher
WILEY
DOI: 10.15252/embj.201694408
Keywords
cancer; FAD biosynthesis; HIF-1; hypoxia; LSD1
Categories
Funding
- National Research Foundation of Korea - Ministry of Science, ICT & Future Planning [NRF-2013R1A1A 1006638, NRF-2013M3A9B5076422, NRF-2016M3A9E4947789, NRF-2016R1A5A2012284]
- KRIBB Research Initiative Program
- National Research Council of Science & Technology (NST), Republic of Korea [C37100] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2016M3A9E4947789, 2013M3A9B5076422] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-1 alpha. 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-1 alpha downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1 alpha stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1 alpha 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-1 alpha stability.
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