MUC16 C terminal fragment activates YAP1 through Src signaling to promote gallbladder cancer growth

Author:

Fan Kun12345ORCID,Wang Jiwen23456,Zhu Kaihua16,Ni Xiaojian23456,Shen Sheng23456,Gong Zijun23456,Bo Xiaobo23456,Wang Changcheng23456,Cheng Xi23456,Zhang Cheng23456,Suo Tao23456,Liu Han23456,Ni Xiaoling23456,Liu Houbao12345

Affiliation:

1. Department of General Surgery Central Hospital of Xuhui District Shanghai China

2. Department of General Surgery, Zhongshan Hospital Fudan University Shanghai China

3. Biliary Tract Disease Center of Zhongshan Hospital Fudan University Shanghai China

4. Cancer Center, Zhongshan Hospital Fudan University Shanghai China

5. Biliary Tract Disease Institute Fudan University Shanghai China

6. Shanghai Engineering Research Center of Biliary Tract Minimal Invasive Surgery and Materials Shanghai China

Abstract

AbstractThe Hippo pathway is crucial to organ size control and its dysregulation contributes to tumorigenesis. The aberrant activation of YAP1 was identified in gallbladder cancer (GBC). However, the underlying mechanism and role in GBC remains unclear. The C terminal fragment of Mucin16, also known as carbohydrate antigen 125 (CA125) encoded product, MUC16c, plays extensive roles in tumor initiation and development. Our study showed that MUC16c binding with 14‐3‐3ε disrupted the interaction of 14‐3‐3ε and phosphorylated yes‐associated protein 1 (YAP1), which led to the activation of YAP1 in GBC. Furthermore, MUC16c decreased the phosphorylation of YAP1 at serine 397 (ser397) by inhibiting LATS1, which upregulated YAP1 protein stability. Interestingly, there was a potential Src kinase site in the MUC16c fragment. The MUC16c_del15Y polypeptides with the deletion of the Src kinase site promoted the interaction of YAP1 with 14‐3‐3ε and downregulated the YAP1 protein levels. Consistently, SU6656, a Src kinase inhibitor also blocked the activation of YAP1 by MUC16c. The MUC16c_del15Y polypeptides decreased GBC cell proliferation in vitro and the growth of xenograft tumors in vivo. Our study revealed the underlying mechanism of the activation of MUC16c on YAP1 mediated by Src signaling and the antitumor effect of MUC16c_del15Y, providing a potential target for GBC therapy.

Funder

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Publisher

Wiley

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