锌指蛋白 191 通过连接蛋白 1 介导的 Yes 相关蛋白失活抑制肝癌转移。

Zinc finger protein 191 inhibits hepatocellular carcinoma metastasis through discs large 1-mediated yes-associated protein inactivation.

机构信息

State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, PR China.

Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, PR China.

出版信息

Hepatology. 2016 Oct;64(4):1148-62. doi: 10.1002/hep.28708. Epub 2016 Aug 2.

DOI:10.1002/hep.28708

PMID:27358034

Abstract

UNLABELLED

Interplay between cell polarity module Scribble-Lethal Giant Larvae-Discs Large 1 (DLG1) and Yes-associated protein (YAP) appears critical in tumor metastasis. We identified zinc finger protein 191 (ZNF191) as a metastasis suppressor acting through DLG-YAP crosstalk in hepatocellular carcinoma (HCC). Overexpression of ZNF191 in HCC cells impaired cell motility, while ZNF191 depletion promoted cell migration in vitro and metastasis in vivo through triggering YAP signaling. Chromatin immunoprecipitation-sequencing revealed that ZNF191 specifically bound to the promoter of DLG1, a cell polarity maintainer and a negative regulator of YAP. The binding sequence of ZNF191 at the DLG1 promoter is a seven-repeat of TCAT motif. Double-knockdown experiments inferred that DLG1 was not only the mediator of the function of ZNF191 to suppress migration but also a link between ZNF191 and YAP signaling. Decreased expression of ZNF191 in human metastatic HCC specimens correlated positively with DLG1 levels but inversely with YAP activation. Our findings illustrate a YAP-targeting, antimetastasis function of ZNF191, thereby representing a possible prognostic marker and a potential target for metastasis therapy.

CONCLUSION

ZNF191 directly binds to the DLG1 promoter at a typical TCAT repeating motif and activates the expression of DLG1; through up-regulating DLG1, ZNF191 inhibits cell migration and YAP activation in HCC cells and eventually inhibits metastasis. (Hepatology 2016;64:1148-1162).

摘要

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细胞极性模块 Scribble-Lethal Giant Larvae-Discs Large 1 (DLG1) 和 Yes-associated protein (YAP) 之间的相互作用在肿瘤转移中似乎至关重要。我们发现锌指蛋白 191 (ZNF191) 是一种通过 DLG-YAP 串扰在肝细胞癌 (HCC) 中发挥作用的转移抑制因子。ZNF191 在 HCC 细胞中的过表达会损害细胞迁移能力，而 ZNF191 的缺失会通过触发 YAP 信号促进细胞迁移体外和体内转移。染色质免疫沉淀测序显示，ZNF191 特异性结合到细胞极性维持者和 YAP 的负调节剂 DLG1 的启动子上。ZNF191 在 DLG1 启动子上的结合序列是一个七重复的 TCAT 基序。双敲除实验推断，DLG1 不仅是 ZNF191 抑制迁移功能的介导物，也是 ZNF191 和 YAP 信号之间的联系。在人类转移性 HCC 标本中，ZNF191 的表达减少与 DLG1 水平呈正相关，与 YAP 激活呈负相关。我们的研究结果说明了 ZNF191 具有靶向 YAP 的抗转移功能，因此可能是一个潜在的预后标志物和转移治疗的潜在靶点。