Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression.

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

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Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression.

Author: Meijia QIAN ¹ ; Fangjie YAN ² ; Weihua WANG ¹ ; Jiamin DU ¹ ; Tao YUAN ¹ ; Ruilin WU ¹ ; Chenxi ZHAO ¹ ; Jiao WANG ¹ ; Jiabin LU ¹ ; Bo ZHANG ³ ; Nengming LIN ³ ; Xin DONG ⁴ ; Xiaoyang DAI ¹ ; Xiaowu DONG ¹ ; Bo YANG ¹ ; Hong ZHU ¹ ; Qiaojun HE ¹
Author Information

1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
2. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China.
3. Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China.
4. Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Publication Type:Journal Article
Keywords: CCA, cholangiocarcinoma; Cholangiocarcinoma; DAB, 3,3-diaminobenzidine tetrahydrochloride chromogen; DUB, deubiquitinase; Deubiquitinase; FGFR, fibroblast growth factor receptor; FOLFOX, folinic acid, 5-FU and oxaliplatin; IDH1/2, isocitrate dehydrogenase 1/2; IHC, immunohistochemistry; IP, immunoprecipitation; JOSD2; KRAS, kirsten rat sarcoma 2 viral oncogene homolog; LATS1/2, large tumor suppressor kinase 1/2; MST1/2, mammalian Ste20-like kinases 1/2; OTUB2, otubain-2; PBS, phosphate-buffered saline; PDC, patient derived cell; PDX, patient-derived xenograft; RTV, relative tumor volume; SRB, sulforhodamine B; TAZ, transcriptional co-activator with PDZ-binding motif; TCGA, The Cancer Genome Atlas; USP9X/10/47, ubiquitin-specific peptidase 9X/10/47; YAP, Yes-associated protein; YAP/TAZ; YOD1, ubiquitin thioesterase OTU1; rhJOSD2, recombinant human JOSD2; shRNA, specific hairpin RNA
From: Acta Pharmaceutica Sinica B 2021;11(12):4008-4019
CountryChina
Language:English
Abstract: 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 mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining 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