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

Greenhough, Alexander; Bagley, Clare; Heesom, Kate J; Gurevich, David B; Gay, David; Bond, Mark; Collard, Tracey J; Paraskeva, Chris; Martin, Paul; Sansom, Owen J; Malik, Karim; Williams, Ann C

Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis Thumbnail


Authors

Clare Bagley

Kate J Heesom

David B Gurevich

David Gay

Mark Bond

Tracey J Collard

Chris Paraskeva

Paul Martin

Owen J Sansom

Karim Malik

Ann C Williams



Abstract

© 2018 The Authors. Published under the terms of the CC BY 4.0 license 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 invitro and invivo, 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.

Journal Article Type Article
Acceptance Date Jul 27, 2018
Online Publication Date Aug 24, 2018
Publication Date Nov 1, 2018
Deposit Date Feb 12, 2019
Publicly Available Date Feb 14, 2019
Journal EMBO Molecular Medicine
Print ISSN 1757-4676
Electronic ISSN 1757-4684
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 10
Issue 11
Article Number e8699
DOI https://doi.org/10.15252/emmm.201708699
Keywords cancer, GPRC5A, HIF, hypoxia, YAP
Public URL https://uwe-repository.worktribe.com/output/857453
Publisher URL https://doi.org/10.15252/emmm.201708699
Related Public URLs http://www.bristol.ac.uk/news/2018/august/hypoxia.html
Additional Information Additional Information : Corresponding author (Lead contact): E-mail: a.greenhough@bristol.ac.uk
Contract Date Feb 12, 2019

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