Regulation of Hippo/YAP axis in colon cancer progression by the deubiquitinase JOSD1.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2024-08-14 DOI:10.1038/s41420-024-02136-7

Yanan Sun, Dongyi Liu, Xiaobo Zhang, Peng Su, Xin Li, Zhongbo Li, Yingwen Gai, Jingying Li, Zhiyong Yang, Yinlu Ding, Jian Zhu, Xiaodong Tan

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Abstract

Colon cancer is a prevalent malignancy, while recent studies revealed the dys-regulation of Hippo signaling as the important driver for colon cancer progression. Several studies have indicated that post-translational modifications on YAP play crucial roles in both Hippo signaling activity and cancer progression. This raises a puzzling question about why YAP/TAZ, an auto-inhibitory pathway, is frequently over-activated in colon cancer, despite the suppressive cascade of Hippo signaling remaining operational. The protein stability of YAP is subject to a tiny balance between ubiquitination and deubiquitination processes. Through correlation analysis of DUBs (deubiquitinases) expression and Hippo target gene signature in colon cancer samples, we found JOSD1 as a critical deubiquitinase for Hippo signaling and colon cancer progression. JOSD1 could facilitate colon cancer progression and in colon cancer, inhibition of JOSD1 via shRNA has been demonstrated to impede tumorigenesis. Furthermore, molecular mechanism studies have elucidated that JOSD1 enhances the formation of the Hippo/YAP transcriptome by impeding K48-linked polyubiquitination on YAP. ChIP assays have shown that YAP binds to JOSD1's promoter region, promoting its gene transcription. These results suggest that JOSD1 is involved in both activating and being targeted by the Hippo signaling pathway in colon cancer. Consequently, a positive regulatory loop between JOSD1 and Hippo signaling has been identified, underscoring their interdependence during colon cancer progression. Thus, targeting JOSD1 may represent a promising therapeutic approach for managing colon cancer.

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去泛素化酶 JOSD1 在结肠癌进展过程中对 Hippo/YAP 轴的调控。

结肠癌是一种常见的恶性肿瘤，而最近的研究发现，Hippo 信号传导失调是结肠癌进展的重要驱动因素。一些研究表明，YAP 的翻译后修饰在 Hippo 信号活动和癌症进展中起着至关重要的作用。这就提出了一个令人费解的问题：为什么在结肠癌中，尽管 Hippo 信号的抑制级联仍在起作用，但 YAP/TAZ 这一自动抑制通路却经常被过度激活？YAP蛋白的稳定性受泛素化和去泛素化过程之间微小平衡的影响。通过对结肠癌样本中 DUBs（去泛素化酶）表达和 Hippo 靶基因特征的相关性分析，我们发现 JOSD1 是 Hippo 信号转导和结肠癌进展的关键去泛素化酶。在结肠癌中，通过 shRNA 抑制 JOSD1 可阻碍肿瘤发生。此外，分子机制研究已经阐明，JOSD1 通过阻碍 YAP 上与 K48 链接的多泛素化来增强 Hippo/YAP 转录组的形成。ChIP 分析表明，YAP 与 JOSD1 的启动子区域结合，促进其基因转录。这些结果表明，在结肠癌中，JOSD1 既参与激活 Hippo 信号通路，也被 Hippo 信号通路锁定。因此，JOSD1 和 Hippo 信号转导之间的正向调节环已被确定，强调了它们在结肠癌进展过程中的相互依存关系。因此，以 JOSD1 为靶点可能是治疗结肠癌的一种很有前景的方法。

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

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.