EphA2‐to‐YAP pathway drives gastric cancer growth and therapy resistance. Issue 7 (23rd August 2019)

• Record Type: Journal Article
• Authors: Huang, Changhao; Yuan, Weijie; Lai, Chen; Zhong, Shangwei; Yang, Chen; Wang, Ran; Mao, Linfeng; Chen, Zihua; Chen, Zhikang
• Is Part Of: International journal of cancer. Volume 146:Issue 7(2020)
• Page Start: 1937
• Page End: 1949
• Publication Date: 2019-08-23
• Subjects: EphA2 -- YAP -- chemoresistance -- phosphorylation -- gastric cancer; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32609
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin ‐ producing hepatocellular receptor A2 ( EphA2 ) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC. Abstract : What's new? The discovery of novel molecular targets is fundamental to the continued advance of therapeutic agents for gastric cancer (GC). In this study, the authors identify a pathway involving interaction between EphA2, a member of the erythropoietin‐producing hepatocellular receptor family, and yes‐associated protein (YAP) as a promising therapeutic target for GC. In GC cells, EphA2 phosphorylation of YAP protein resulted in YAP stabilization, translocation to the nucleus, and activation. Increased YAP stabilization and nuclear concentration in GC cells and mouse models was further associated with EphA2‐induced chemoresistance. In patients, EphA2 overexpression and nuclear YAP accumulation was related to GC relapse.