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

doi:10.1016/j.apsb.2021.04.003

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Acta Pharm Sin B. 2021 Dec;11(12):4008-4019. doi: 10.1016/j.apsb.2021.04.003. Epub 2021 Jun 25.

Authors

Meijia Qian¹, Fangjie Yan², Weihua Wang¹, Jiamin Du¹, Tao Yuan¹, Ruilin Wu¹, Chenxi Zhao¹, Jiao Wang¹, Jiabin Lu¹, Bo Zhang³, Nengming Lin³, Xin Dong⁴, Xiaoyang Dai¹, Xiaowu Dong¹, Bo Yang¹, Hong Zhu^{1

3

5}, Qiaojun He^{1

2

4

5}

Affiliations

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.
⁵ Cancer Center of Zhejiang University, Hangzhou 310058, China.

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 in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, 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.

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.