Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis.
Cancer cell adaptation to hypoxia involves a HIF-GPRC5A-YAP axis.
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DOI：
10.15252/emmm.201708699
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发表时间：
2018-11
影响因子：
11.1
通讯作者：
Williams AC
中科院分区：
文献类型：
--
作者：
Greenhough A;Bagley C;Heesom KJ;Gurevich DB;Gay D;Bond M;Collard TJ;Paraskeva C;Martin P;Sansom OJ;Malik K;Williams AC
缺氧是实体瘤的标志，也是区分肿瘤与正常组织的关键生理特征。然而，一个主要的挑战仍然是确定缺氧癌细胞赖以生存的可处理的分子靶点。在这里，我们使用基于SILAC的蛋白质组学方法鉴定了孤儿G蛋白偶联受体GPRC5A作为一种新的缺氧诱导蛋白，其功能是在缺氧时保护癌细胞免于凋亡。通过体外和体内的遗传方法，我们发现hif是GPRC5A转录的直接激活因子。此外，我们发现GPRC5A在肠系膜缺血患者的结肠上皮中表达上调，在结直肠癌中，高GPRC5A与缺氧基因特征和不良临床结果相关。在机制上，我们发现GPRC5A通过激活Hippo通路效应物YAP及其抗凋亡靶基因BCL2L1来促进缺氧细胞存活。重要的是，我们发现缺氧时GPRC5A缺失诱导的细胞凋亡可以通过组成型活性YAP来挽救。我们的研究确定了一种新的HIF - GPRC5A - YAP轴作为缺氧诱导的适应性反应的关键介质和癌症治疗的潜在靶点。
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.
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DOI：
10.1074/jbc.m901790200
发表时间：
2009-06-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mole DR;Blancher C;Copley RR;Pollard PJ;Gleadle JM;Ragoussis J;Ratcliffe PJ
通讯作者：
Ratcliffe PJ
影响因子：
11.1
作者：
McIntyre A;Harris AL
通讯作者：
Harris AL
影响因子：
64.5
作者：
Rosenbluh J;Nijhawan D;Cox AG;Li X;Neal JT;Schafer EJ;Zack TI;Wang X;Tsherniak A;Schinzel AC;Shao DD;Schumacher SE;Weir BA;Vazquez F;Cowley GS;Root DE;Mesirov JP;Beroukhim R;Kuo CJ;Goessling W;Hahn WC
通讯作者：
Hahn WC
DOI：
10.1073/pnas.0807833105
发表时间：
2008-10-07
影响因子：
11.1
作者：
Kohyama-Koganeya, Ayako;Kim, Yeon-Jeong;Hirabayashi, Yoshio
通讯作者：
Hirabayashi, Yoshio
影响因子：
5
作者：
Kimura TE;Duggirala A;Smith MC;White S;Sala-Newby GB;Newby AC;Bond M
通讯作者：
Bond M