DUB1 suppresses Hippo signaling via modulating TAZ protein in gastric cancer

The Hippo pathway functions as a tumor-suppressor pathway in human cancers, while the dys-function of Hippo pathway is frequently observed in malignancies. Although the YAP/TAZ activity is tightly controlled by the phosphorylation cascade of MST-LATS-YAP/TAZ axis, it is still unclear why YAP/TAZ protein is activated in human cancers, even Hippo pathway is still active. Besides phosphorylation, recent studies implicate that several post-translational modifications also play critical roles in modulating TAZ function, including ubiquitination. Here, by a DUB (Deubiquitinases) siRNA screening library, we discovered DUB1 as a critical modulator to facilitate gastric cancer stemness and progression, which deubiquitinated and activated TAZ protein. We also identified DUB1 was elevated in gastric cancer, which correlated with TAZ activation and poor survival. DUB1 associated with TAZ protein and deubiquitinated TAZ at several lysine sites, which subsequently stabilized and facilitated TAZ function. Our study revealed a novel deubiquitinase of Hippo/TAZ axis and one possible therapeutic target for Hippo-driven gastric cancer. Overall design: Gastric cancer cell mRNA samples were summarized in six samples, divided into two groups, siControl and siDUB1

Hippo信号通路（Hippo pathway）在人类癌症中作为抑癌通路发挥作用，其功能异常在恶性肿瘤中颇为常见。尽管YAP/TAZ的活性受MST-LATS-YAP/TAZ轴的磷酸化级联反应严格调控，但目前仍未阐明：为何在人类癌症中，即便Hippo信号通路仍处于激活状态，YAP/TAZ蛋白仍会被激活。除磷酸化修饰外，近期研究显示多种翻译后修饰在调控TAZ功能中扮演关键角色，泛素化修饰即为其中之一。本研究借助去泛素化酶（Deubiquitinases，DUB）siRNA筛选文库，鉴定出DUB1是调控胃癌干细胞干性与疾病进展的关键调节因子，其可通过去泛素化修饰激活TAZ蛋白。研究证实DUB1在胃癌组织中表达上调，且该现象与TAZ激活及患者不良预后显著相关。DUB1可与TAZ蛋白结合，并在TAZ的多个赖氨酸位点介导去泛素化修饰，进而稳定TAZ蛋白并增强其生物学功能。本研究揭示了Hippo/TAZ轴的新型去泛素化调控机制，同时为Hippo通路驱动型胃癌提供了潜在治疗靶点。
实验整体设计：本研究收集6份胃癌细胞mRNA样本，分为两组，即阴性对照siRNA（siControl）组与DUB1敲低siRNA（siDUB1）组。