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

• Published in: EMBO molecular medicine Vol. 10; no. 11; pp. 1 - n/a
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2018; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Adaptation; Adaptation, Physiological - drug effects; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens, Neoplasm - metabolism; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cancer; Cancer therapies; Carbonic Anhydrase IX - metabolism; Cell Hypoxia - drug effects; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Doxycycline - pharmacology; EMBO03; EMBO46; Epithelium; GPRC5A; HIF; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Ischemia; Mice, Inbred C57BL; Models, Biological; Neoplasms - genetics; Neoplasms - pathology; Oxygen; Phosphoproteins - metabolism; Physiology; Proteins; Proteomics; Receptors, G-Protein-Coupled - metabolism; Research Article; RhoA protein; Signal transduction; Signal Transduction - drug effects; Solid tumors; Transcription Factors; Transcription, Genetic - drug effects; YAP; YAP-Signaling Proteins; Yes-associated protein; Zebrafish; hypoxia; YAP; cancer; GPRC5A; HIF
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201708699

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.
Synopsis
This study identifies a novel hypoxia‐activated signalling axis that facilitates the adaptation of tumour cells to low oxygen conditions. HIFs directly induce the expression of orphan receptor GPRC5A, which signals via Hippo pathway effector YAP to protect hypoxic tumour cells from apoptosis.
Orphan G protein‐coupled receptor GPRC5A is induced by hypoxia
in vitro
and
in vivo
.
HIFs are major and direct physiological regulators of GPRC5A expression.
Depletion of GPRC5A promotes apoptosis in hypoxic cancer cells.
GPRC5A activates YAP via RhoA to suppress apoptosis via BCL‐XL induction.
GPRC5A is a potentially druggable target to exploit tumour‐associated hypoxia for cancer therapy.
Graphical Abstract
This study identifies a novel hypoxia‐activated signalling axis that facilitates the adaptation of tumour cells to low oxygen conditions. HIFs directly induce the expression of orphan receptor GPRC5A, which signals via Hippo pathway effector YAP to protect hypoxic tumour cells from apoptosis.