食管鳞癌(ESCC)是我国食管癌的主要亚型,占90%。最近的研究表明,Hippo/YAP 轴的异常在 ESCC 中普遍存在,并且被认为是 ESCC 进展的重要驱动因素。由于 Hippo 信号的活动受磷酸化级联控制,因此当级联被抑制时,主要效应器 YAP 仍然过度激活的原因是一个谜。多项研究表明,除了磷酸化之外,泛素化等其他蛋白质修饰也在操纵 Hippo/YAP 信号活性中发挥重要作用。由于 YAP 蛋白的稳定性是通过 E3 泛素连接酶和去泛素酶之间的适当平衡来控制的,我们进行了去泛素化酶 siRNA 筛选,并将 USP36 鉴定为与 Hippo/YAP 信号活性和 ESCC 进展显着相关的去泛素化酶。USP36 表达在 ESCC 样本中升高并且与分化差相关。USP36 表达与 ESCC 样本中的 YAP 蛋白水平相关。分子研究表明,USP36 与 YAP 蛋白相关,并通过阻断 YAP 的 K48 连接多聚泛素化来增强 YAP 蛋白稳定性。总之,我们的研究揭示了一种新的去泛素化酶在 ESCC 中调节 Hippo 信号,这可能是 Hippo 驱动的 ESCC 的一个令人鼓舞的药物靶点。分子研究表明,USP36 与 YAP 蛋白相关,并通过阻断 YAP 的 K48 连接多聚泛素化来增强 YAP 蛋白稳定性。总之,我们的研究揭示了一种新的去泛素化酶在 ESCC 中调节 Hippo 信号,这可能是 Hippo 驱动的 ESCC 的一个令人鼓舞的药物靶点。分子研究表明,USP36 与 YAP 蛋白相关,并通过阻断 YAP 的 K48 连接多聚泛素化来增强 YAP 蛋白稳定性。总之,我们的研究揭示了一种新的去泛素化酶在 ESCC 中调节 Hippo 信号,这可能是 Hippo 驱动的 ESCC 的一个令人鼓舞的药物靶点。
"点击查看英文标题和摘要"
USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP
Esophageal squamous carcinoma (ESCC) is the major subtype of esophageal cancer in China, accounting for 90% of cases. Recent studies revealed that abnormalities in the Hippo/YAP axis are pervasive in ESCC and are recognized as the important driver of ESCC progression. Since the activity of Hippo signaling is controlled by phosphorylation cascade, it is a mystery why the major effector YAP is still over-activated when the cascade is inhibited. Several studies suggested that in addition to phosphorylation, other protein modifications such as ubiquitination also play important roles in manipulating Hippo/YAP signaling activity. Since YAP protein stability is controlled via an appropriate balance between E3 ubiquitin ligases and deubiquitinases, we performed deubiquitinase siRNA screening and identified USP36 as a deubiquitinase significantly related to Hippo/YAP signaling activity and ESCC progression. USP36 expression was elevated in ESCC samples and correlated with poor differentiation. USP36 expression was correlated with YAP protein levels in ESCC samples. Molecular studies demonstrated that USP36 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. In conclusion, our study revealed a novel deubiquitinase in regulating Hippo signaling in ESCC, which could be an encouraging drug target for Hippo-driven ESCC.