Sun Yanan, Liu Dongyi, Zhang Xiaobo, Su Peng, Li Xin, Li Zhongbo, Gai Yingwen, Li Jingying, Yang Zhiyong, Ding Yinlu, Zhu Jian, Tan Xiaodong
Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong Province, P.R. China.
Department of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong Province, P.R. China.
Cell Death Discov. 2024 Aug 14;10(1):365. doi: 10.1038/s41420-024-02136-7.
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.
结肠癌是一种常见的恶性肿瘤，而最近的研究表明，Hippo信号通路的失调是结肠癌进展的重要驱动因素。多项研究表明，YAP的翻译后修饰在Hippo信号活性和癌症进展中都起着关键作用。这就引发了一个令人困惑的问题：尽管Hippo信号的抑制级联仍然有效，但作为一种自抑制途径的YAP/TAZ在结肠癌中为何经常过度激活。YAP的蛋白质稳定性取决于泛素化和去泛素化过程之间的微小平衡。通过对结肠癌样本中去泛素化酶（DUBs）表达与Hippo靶基因特征的相关性分析，我们发现JOSD1是Hippo信号通路和结肠癌进展的关键去泛素化酶。JOSD1可以促进结肠癌进展，并且在结肠癌中，通过短发夹RNA抑制JOSD1已被证明会阻碍肿瘤发生。此外，分子机制研究表明，JOSD1通过阻止YAP上K48连接的多聚泛素化来增强Hippo/YAP转录组的形成。染色质免疫沉淀分析表明，YAP与JOSD1的启动子区域结合，促进其基因转录。这些结果表明，JOSD1在结肠癌中既参与激活Hippo信号通路，又被该信号通路靶向。因此，已确定JOSD1与Hippo信号通路之间存在正调控环，强调了它们在结肠癌进展过程中的相互依赖性。因此，靶向JOSD1可能是治疗结肠癌的一种有前景的治疗方法。
