2. Academic Validation
  3. Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis

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

  • EMBO Mol Med. 2018 Nov;10(11):e8699. doi: 10.15252/emmm.201708699.
Alexander Greenhough 1 2,  Clare Bagley 3,  Kate J Heesom 4,  David B Gurevich 5,  David Gay 6,  Mark Bond 7,  Tracey J Collard 3,  Chris Paraskeva 3,  Paul Martin 5 8 9,  Owen J Sansom 6 10,  Karim Malik 11,  Ann C Williams 1
Affiliations

Affiliations

  • 1 Cancer Research UK Colorectal Tumour Biology Group, School of Cellular & Molecular Medicine, Faculty of Life Sciences University of Bristol, Bristol, UK a.greenhough@bristol.ac.uk k.t.a.malik@bristol.ac.uk ann.c.williams@bristol.ac.uk.
  • 2 Cancer Epigenetics Laboratory, School of Cellular & Molecular Medicine, Faculty of Life Sciences University of Bristol, Bristol, UK.
  • 3 Cancer Research UK Colorectal Tumour Biology Group, School of Cellular & Molecular Medicine, Faculty of Life Sciences University of Bristol, Bristol, UK.
  • 4 Proteomics Facility, Faculty of Life Sciences University of Bristol, Bristol, UK.
  • 5 School of Biochemistry, Faculty of Life Sciences University of Bristol, Bristol, UK.
  • 6 Cancer Research UK Beatson Institute, Glasgow, UK.
  • 7 School of Clinical Sciences, University of Bristol, Bristol, UK.
  • 8 School of Physiology, Pharmacology and Neuroscience, Faculty of Life Sciences University of Bristol, Bristol, UK.
  • 9 School of Medicine, Cardiff University, Cardiff, UK.
  • 10 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 11 Cancer Epigenetics Laboratory, School of Cellular & Molecular Medicine, Faculty of Life Sciences University of Bristol, Bristol, UK a.greenhough@bristol.ac.uk k.t.a.malik@bristol.ac.uk ann.c.williams@bristol.ac.uk.
PMID: 30143543 DOI: 10.15252/emmm.201708699
Abstract

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.

Keywords

GPRC5A; HIF; YAP; cancer; hypoxia.

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