Cezanne regulates E2F1-dependent HIF2α expression

• DOI: 10.1242/jcs.168864
• Publication Date: 2015-07-07T00:30:06Z
• Authors: Sonia Moniz; Daniel Bandarra; John Biddlestone; Kirsteen J. Campbell; David Komander; Anja Bremm; Sonia Rocha
• Keywords: 0301 basic medicine; Cezanne; 570; HIFα; ChIP; Cell Cycle Checkpoints; Cell cycle; Cell Hypoxia; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; HEK293 Cells; E2F1; ddc:570; Endopeptidases; Proteolysis; Basic Helix-Loop-Helix Transcription Factors; Humans; ddc:570; Hypoxia; Promoter Regions, Genetic; E2F1 Transcription Factor; Research Article; HeLa Cells

Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal oxygen tensions, HIFα subunits are targeted for proteasomal degradation mainly by vHL-dependent ubiquitination. Deubiquitinases are responsible for reversing this process. While the mechanism and regulation of HIFα ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitinases. Here we show that HIF2α expression is regulated by the deubiquitinase Cezanne in an E2F1-dependent manner. Knockdown of Cezanne down-regulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, HIF2α gene expression 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. Together these data reveal a novel mechanism for the regulation of HIF2α expression, demonstrating that HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression via 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.