JOSD1 facilitates colorectal cancer progression via stabilizing YAP

Colorectal cancer is one of the most lethal human malignancies in the world. Although great efforts are put in developing novel therapeutic targets, the effective targeting drugs are still limited. Recent studies reveal the abnormality of Hippo/YAP axis play critical role in the oncogenic process of Colorectal cancer. It is of great importance to demonstrate the regulation of Hippo signaling activity and YAP protein turnover in Colorectal cancer. Besides, the phosphorylation cascade on YAP function, which has been thoroughly investigated, the ubiquitination of YAP is also important in Hippo signaling status. Here, We utilized the DUB (Deubiquitinase) siRNA library to identify critical DUB for Hippo signaling. We discovered JOSD1 as a critical factor to facilitate Colorectal cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein. The clinical data analysis implicated JOSD1 was correlated with YAP activity and poor survival. Molecular studies demonstrated that JOSD1 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. Our study revealed a novel deubiquitinase of Hippo/YAP axis and one possible therapeutic target for YAP-driven Colorectal cancer