Cancer Research UK Colorectal Tumour Biology Group, School of Cellular & Molecular Medicine, Faculty of Life Sciences University of Bristol, Bristol, UK
Cancer Epigenetics Laboratory, School of Cellular & Molecular Medicine, Faculty of Life Sciences University of Bristol, Bristol, UK.
EMBO Mol Med. 2018 Nov;10(11). 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 and , we reveal HIFs as direct activators of transcription. Furthermore, we find that GPRC5A is upregulated in the colonic epithelium of patients with mesenteric ischaemia, and in colorectal cancers high 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 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.
缺氧是实体瘤的一个标志，也是将癌症与正常组织区分开来的关键生理特征。然而，确定可治疗的分子靶标仍然是一个主要挑战，这些靶标是缺氧癌细胞生存所依赖的。在这里，我们使用基于 SILAC 的蛋白质组学鉴定了孤儿 G 蛋白偶联受体 GPRC5A 作为一种新的缺氧诱导蛋白，它在缺氧时保护癌细胞免于凋亡。使用遗传方法和小分子抑制剂，我们揭示了 HIFs 是转录的直接激活剂。此外，我们发现 GPRC5A 在肠系膜缺血患者的结肠上皮和结直肠癌细胞中上调，并且在结直肠癌中高与缺氧基因特征和不良临床结果相关。在机制上，我们表明 GPRC5A 通过激活 Hippo 通路效应物 YAP 及其抗凋亡靶基因 来使缺氧细胞存活。重要的是，我们表明在缺氧时 GPRC5A 耗竭诱导的细胞凋亡可以通过组成型激活的 YAP 挽救。我们的研究确定了一个新的 HIF-GPRC5A-YAP 轴作为缺氧诱导适应性反应的关键介质，以及癌症治疗的潜在靶点。
