Cezanne regulates E2F1-dependent HIF2α expression

Sonia Moniz, Daniel Bandarra, John Biddlestone, Kirsteen J Campbell, David Komander, Anja Bremm, Sonia Rocha (Lead / Corresponding author)

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    Abstract

    Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling.

    Original languageEnglish
    Article numberJOCES/2015/168864
    Pages (from-to)3082-3093
    Number of pages12
    JournalJournal of Cell Science
    Volume128
    Issue number16
    Early online date6 Jul 2015
    DOIs
    Publication statusPublished - 15 Aug 2015

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    Keywords

    • HIFα
    • Cezanne
    • Hypoxia
    • Cell cycle
    • E2F1
    • ChIP
    • cell cycle

    Cite this

    Moniz, S., Bandarra, D., Biddlestone, J., Campbell, K. J., Komander, D., Bremm, A., & Rocha, S. (2015). Cezanne regulates E2F1-dependent HIF2α expression. Journal of Cell Science, 128(16), 3082-3093. [JOCES/2015/168864]. https://doi.org/10.1242/jcs.168864