Open AccessEnzyme 15‐lipoxygenase 1 promotes hypoxia‐inducible factor 1 α turnover and reduces vascular endothelial growth factor expression: implications for angiogenesis
Author(s) -
Zhong Hua,
Wang Ruoxiang,
Kelavkar Uddhav,
Wang Christopher Y.,
Simons Jonathan
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.227
Subject(s) - angiogenesis , hypoxia inducible factors , lipoxygenase , hypoxia inducible factor 1 , hydroxylation , cellular adaptation , microbiology and biotechnology , biology , hypoxia (environmental) , enzyme , vascular endothelial growth factor , biochemistry , chemistry , transcription factor , cancer research , gene , vegf receptors , oxygen , organic chemistry
Abstract Hypoxia‐inducible factor 1 α ( HIF ‐1 α ) is the regulatory subunit of the heterodimeric HIF ‐1 that plays a critical role in transcriptional regulation of genes in angiogenesis and hypoxic adaptation, while fatty acid metabolism mediated by lipoxygenases has been implicated in a variety of pathogeneses, including cancers. In this study, we report that 15‐lipoxygenase 1 (15‐ LO 1), a key member of the lipoxygenase family, promotes HIF ‐1 α ubiquitination and degradation. Altering the level of 15‐ LO 1 yields inverse changes in HIF ‐1 α and HIF ‐1 transcriptional activity, under both normoxia and hypoxia, and even in CoCl 2 ‐treated cells where HIF ‐1 α has been artificially elevated. The antagonistic effect of 15‐ LO 1 is mediated by the Pro 564 /hydroxylation/26S proteasome system, while both the enzymatic activity and the intracellular membrane‐binding function of 15‐ LO 1 appear to contribute to HIF ‐1 α suppression. Our findings provide a novel mechanism for HIF ‐1 α regulation, in which oxygen‐dependent HIF ‐1 activity is modulated by an oxygen‐insensitive lipid metabolic enzyme.