The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xu Li, Yong Suk Cho, Yuhong Han, Mengmeng Zhou, Yuchen Liu, Yingzi Yang, Shu Zhuo, Jin Jiang
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引用次数: 0

Abstract

The prevailing view in the cancer field is that Hippo signaling pathway functions as a tumor suppressor pathway by blocking the oncogenic potential of the pathway effectors Yes1 associated transcriptional regulator (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). We find that, in additional to inhibiting hypoxia-inducible factor 2α (HIF2α), a major oncogenic driver in Von Hippel-Lindau (VHL)-/- ccRCC, YAP also blocks nuclear factor κB (NF-κB) signaling in ccRCC to inhibit cancer cell growth under conditions where HIF2α is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a VHL substrate and critical co-factor of NF-κB in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-κB subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-κB subunit p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hippo kinase blocked NF-κB transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by overexpression of ZHX2 or p65. Our study uncovers a crosstalk between the Hippo and NF-κB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.

Hippo通路效应物YAP通过对抗ZHX2抑制NF-κB信号和ccRCC生长。
癌症领域的主流观点是,Hippo信号通路通过阻断通路效应物Yes1相关转录调节因子(YAP)/带pdz结合基序的转录共激活因子(TAZ)的致癌潜能而发挥肿瘤抑制通路的作用。然而,在包括透明细胞肾细胞癌(ccRCC)在内的几种类型的癌症中,YAP也可以作为上下文依赖的肿瘤抑制因子发挥作用。我们发现,除了抑制Von Hippel-Lindau (VHL)-/- ccRCC的主要致癌驱动因子-缺氧诱导因子2α (HIF2α)外,YAP还阻断ccRCC中的核因子κB (NF-κB)信号传导,从而在不需要HIF2α的情况下抑制癌细胞生长。在机制上,YAP抑制锌指和同源盒2 (ZHX2)的表达,ZHX2是VHL底物和NF-κB在ccRCC中的关键辅助因子。此外,YAP与ZHX2竞争与NF-κB亚基p65的结合。因此,核YAP的升高阻断了ZHX2与NF-κB亚基p65之间的协同作用,导致NF-κB靶基因表达减少。药理抑制Hippo激酶阻断NF-κB转录程序,抑制ccRCC癌细胞生长,可通过过表达ZHX2或p65来挽救。我们的研究揭示了Hippo和NF-κB/ZHX2通路之间的串扰及其参与ccRCC生长抑制,表明靶向Hippo通路可能为ccRCC治疗提供治疗机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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