Identification of novel regulators of HIFs for use in anti-cancer target development
Solid tumours display vast heterogeneity in oxygen tension as a consequence of poor vascularization and increased proliferation. Tumour hypoxia (low oxygen) is associated with poor prognosis as cells within this harsh microenvironment are viable and often resistant to chemotherapy and radiotherapy. The cellular response to hypoxia is regulated by transcription factors called hypoxia inducible factor (HIF). HIF is a heterodimeric protein consisting of an O2-labile subunit (HIF-1α, HIF-2α and HIF-3α) and a beta subunit (HIF-1β). Expression of either HIF-1α or HIF-2α often correlates with poor prognosis. HIFα is degraded by a well characterized pathway, however numerous studies have shown multiple novel regulators that also effect HIF activity and stability. Such novel regulators could therefore represent new therapeutic targets for the development of novel anti-cancer therapies for those tumours with high levels of hypoxia. In order to identify novel regulators of HIF, we undertook an unbiased approached and performed an RNAi kinome screen. Through this, we identified the bifunctional enzyme Coenzyme A synthase (CoAsy) as a novel negative regulator of HIF-1 transcriptional activity. Knockdown of CoAsy stabilizes both HIF-1α and HIF-2α in normoxia and hypoxia with no change in HIF-1β protein levels. Overexpression of PANK1, the rate limiting step in CoA biosynthesis, resulted in reduced HIFα expression thereby highlighting a role of Coenzyme A in regulating HIF stability. Analysis of breast cancer patients shows reduced COASY mRNA expression in the tumour compared to surrounding tissue and furthermore lower CoAsy expression is often found in triple negative breast cancer tumours compared to hormone sensitive tumours. These data indicate that CoAsy is a novel negative regulator of HIFs and highlights a novel link between Coenzyme A biosynthesis and cellular hypoxic response.
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