Alexander Greenhough Alexander.Greenhough@uwe.ac.uk
Associate Professor of Health Diagnostics
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
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 |
Files
e8699.full.pdf
(2.6 Mb)
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