Cancer cell adaptation to hypoxia involves a HIF‐GPRC5A‐YAP axis

Greenhough, A. et al. (2018) Cancer cell adaptation to hypoxia involves a HIF‐GPRC5A‐YAP axis. EMBO Molecular Medicine, 10(11), e8699. (doi: 10.15252/emmm.201708699) (PMID:30143543) (PMCID:PMC6220329)

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Hypoxia is a hallmark of solid tumours and a key physiological feature distinguishing cancer from normal tissue. However, a major challenge remains in identifying tractable molecular targets that hypoxic cancer cells depend on for survival. Here, we used SILAC‐based proteomics to identify the orphan G protein‐coupled receptor GPRC5A as a novel hypoxia‐induced protein that functions to protect cancer cells from apoptosis during oxygen deprivation. Using genetic approaches in vitro and in vivo, we reveal HIFs as direct activators of GPRC5A transcription. Furthermore, we find that GPRC5A is upregulated in the colonic epithelium of patients with mesenteric ischaemia, and in colorectal cancers high GPRC5A correlates with hypoxia gene signatures and poor clinical outcomes. Mechanistically, we show that GPRC5A enables hypoxic cell survival by activating the Hippo pathway effector YAP and its anti‐apoptotic target gene BCL2L1. Importantly, we show that the apoptosis induced by GPRC5A depletion in hypoxia can be rescued by constitutively active YAP. Our study identifies a novel HIF‐GPRC5A‐YAP axis as a critical mediator of the hypoxia‐induced adaptive response and a potential target for cancer therapy.

Item Type:Articles
Additional Information:This work was funded by a Cancer Research UK Programme Grant to ACW and CP (C19/A11975; AG, TJC, ACW and CP) a University of Bristol studentship (to CB), a BBSRC grant to KM (BB/P008232/1; AG and KM) the Citrina Foundation (AG, TJC, ACW and CP) and the John James Bristol Foundation (AG, TJC, ACW and CP). PM is supported by a Wellcome Trust Investigator Award (WT097791/Z11/Z; DBG and PM) and a Cancer Research UK Programme Grant (C20590/A15936). KM is supported by a Cancer Research UK grant (A12743/A21046). OJS is supported by Cancer Research UK grants (C7932/A25045, C596/A17196, A12481 and A21139) and an ERC starting grant (COLONCAN/311301; OJS and DG).
Glasgow Author(s) Enlighten ID:Gay, David and Sansom, Professor Owen
Authors: Greenhough, A., Bagley, C., Heesom, K. J., Gurevich, D. B., Gay, D., Bond, M., Collard, T. J., Paraskeva, C., Martin, P., Sansom, O. J., Malik, K., and Williams, A. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:EMBO Molecular Medicine
Publisher:EMBO Press
ISSN (Online):1757-4684
Published Online:24 August 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in EMBO Molecular Medicine 10(11): e8699
Publisher Policy:Reproduced under a Creative Commons License

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