Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

• 作者: Meijia Qian Fangjie Yan Weihua Wang Jiamin Du Tao Yuan Ruilin Wu Chenxi Zhao Jiao Wang Jiabin Lu Bo Zhang Nengming Lin Xin Dong Xiaoyang Dai Xiaowu Dong Bo Yang Hong Zhu Qiaojun He
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Original articles
• 页码范围: 4008-4019
• 页数: 12页
• 语种: 英文

摘要

Cholangiocarcinoma(CCA)has emerged as an intractable cancer with scanty therapeutic regimens.The aberrant activation of Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)are reported to be common in CCA patients.However,the underpinning mech-anism remains poorly understood.Deubiquitinase(DUB)is regarded as a main orchestrator in maintain-ing protein homeostasis.Here,we identified Josephin domain-containing protein 2(JOSD2)as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner.The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo.Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples.Collec-tively,this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression,which may provide a potential intervention target for YAP/TAZ-related CCA patients.