Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase

Qiong Liu, Hao Geng, Changhui Xue, Tomasz M. Beer, David Z. Qian

    Research output: Contribution to journalArticle

    9 Scopus citations

    Abstract

    HIF-1α is degraded by oxygen-dependent mechanisms but stabilized in hypoxia to form transcriptional complex HIF-1, which transactivates genes promoting cancer hallmarks. However, how HIF-1α is specifically regulated in hypoxia is poorly understood. Here, we report that the histone methyltransferase SET9 promotes HIF-1α protein stability in hypoxia and enhances HIF-1 mediated glycolytic gene transcription, thereby playing an important role in mediating cancer cell adaptation and survival to hypoxic stress. Specifically, SET9 interacts with HIF-1α and promotes HIF-1α protein stability in hypoxia. Silencing SET9 by siRNA reduces HIF-1α protein stability in hypoxia, and attenuates the hypoxic induction of HIF-1 target genes mediating hypoxic glycolysis. Mechanistically, we find that SET9 is enriched at the hypoxia response elements (HRE) within promoters of the HIF-1-responsive glycolytic genes. Silencing SET9 reduces HIF-1α levels at these HREs in hypoxia, thereby attenuating HIF-1-mediated gene transcription. Further, silencing SET9 by siRNA reduces hypoxia-induced glycolysis and inhibits cell viability of hypoxic cancer cells. Our findings suggest that SET9 enriches at HRE sites of HIF-1 responsive glycolytic genes and stabilizes HIF-1α at these sites in hypoxia, thus establishes an epigenetic mechanism of the metabolic adaptation in hypoxic cancer cells.

    Original languageEnglish (US)
    Pages (from-to)881-891
    Number of pages11
    JournalBiochimica et Biophysica Acta - Molecular Cell Research
    Volume1853
    Issue number5
    DOIs
    StatePublished - May 1 2015

    Keywords

    • Cancer
    • Gene regulation
    • Hypoxia
    • Metabolic adaptation
    • Protein interaction
    • Transcription factor

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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