Cezanne regulates E2F1-dependent HIF2α expression

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.

Ubiquitin chain diversity at a glance

“…It has been shown that the K11-linkage-specific DUB Cezanne (OTUD7B) (Bremm et al, 2010;Mevissen et al, 2013) regulates stability of the transcription factor HIF-1α (Bremm et al, 2014) and expression levels of HIF-2α (Moniz et al, 2015). However, in this context, the exact topology of the ubiquitin signal is not yet understood.…”

The role of hypoxia‐inducible factor‐2 alpha in angiogenesis

“…In addition, it has been reported that EPAS1 transcription is regulated by the IGF‐induced PI3K‐mTORC2 system promoting vascularization in neuroblastoma (Mohlin et al, ). The deubiquitylase Cezanne (also known as OTUD7B) is also involved in the regulation of HIF‐2α mRNA synthesis via E2F1, which directly binds to the EPAS1 promoter (Moniz et al, ). Finally, Nakazawa et al () has showed that HIF‐2α expression is epigenetically downregulated via class I/II HDACs, resulting in increased Anoctamin 1 (ANO1), calcium signaling, and elevated mTORC1 activity in tumors promoting sarcoma proliferation (Nakazawa et al, ).…”

Intestine-specific homeobox (ISX) upregulates E2F1 expression and related oncogenic activities in HCC

“…On one hand, E2F1 acts as an inhibitor of hepatitis B virus-mediated HCC by activating p53 expression [18, 19]. In animal models, the TFDP3/E2F1 pathway induces apoptosis in HCC by positively regulating HIF-2α, and the decreased levels of HIF-2α were associated with lower overall survival of HCC animals [20, 21]. On the other hand, overexpression and genome amplification of E2F1 has been observed in HCC [17, 22].…”