Original articles
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. Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 4008-4019

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression
Meijia Qiana, Fangjie Yanb, Weihua Wanga, Jiamin Dua, Tao Yuana, Ruilin Wua, Chenxi Zhaoa, Jiao Wanga, Jiabin Lua, Bo Zhangc, Nengming Linc, Xin Dongd, Xiaoyang Daia, Xiaowu Donga, Bo Yanga, Hong Zhua,c,e, Qiaojun Hea,b,d,e
a. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;
b. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China;
c. 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;
d. Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China;
e. Cancer Center of Zhejiang University, Hangzhou 310058, China
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.
Key words:    Cholangiocarcinoma    Deubiquitinase    JOSD2    YAP/TAZ   
Received: 2020-12-21     Revised: 2021-02-07
DOI: 10.1016/j.apsb.2021.04.003
Funds: We are grateful to Ms. Renhua Gai from Zhejiang University for providing technical assistance in IHC. This work was supported by the Key Program of the Natural Science Foundation of China (No. 81830107), the Natural Science Foundation for Distinguished Young Scholar of China (No. 81625024), the Natural Science Foundation of China (No. 81773753, No. 81973349), and the Zhejiang Provincial Natural Science Foundation (No. LR19H310002 and No. LR21H300003, China).
Corresponding author: Hong Zhu,E-mail:hongzhu@zju.edu.cn;Qiaojun He,E-mail:qiaojunhe@zju.edu.cn     Email:hongzhu@zju.edu.cn;qiaojunhe@zju.edu.cn
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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

[1] Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17: 557-588
[2] Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma-evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 2018; 15: 95-111
[3] Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383: 2168-2179
[4] Kelley RK, Bridgewater J, Gores GJ, Zhu AX. Systemic therapies for intrahepatic cholangiocarcinoma. J Hepatol 2020; 72: 353-363
[5] Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer cell 2016; 29: 783-803
[6] Nguyen CDK, Yi C. YAP/TAZ signaling and resistance to cancer therapy. Trends Cancer 2019; 5: 283-296
[7] Marti P, Stein C, Blumer T, Abraham Y, Dill MT, Pikiolek M, et al. YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors. Hepatology 2015; 62: 1497-1510
[8] Zhao C, Zeng C, Ye S, Dai X, He Q, Yang B, et al. Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ): a nexus between hypoxia and cancer. Acta Pharm Sin B 2020; 10: 947-960
[9] Totaro A, Panciera T, Piccolo S. YAP/TAZ upstream signals and downstream responses. Nat Cell Biol 2018; 20: 888-899
[10] Sugihara T, Isomoto H, Gores G, Smoot R. YAP and the Hippo pathway in cholangiocarcinoma. J Gastroenterol 2019; 54: 485-491
[11] Wu H, Liu Y, Jiang XW, Li WF, Guo G, Gong JP, et al. Clinicopathological and prognostic significance of Yes-associated protein expression in hepatocellular carcinoma and hepatic cholangiocarcinoma. Tumour Biol 2016; 37: 13499-13508
[12] Xiao H, Tong R, Yang B, Lv Z, Du C, Peng C, et al. TAZ regulates cell proliferation and sensitivity to vitamin D3 in intrahepatic cholangiocarcinoma. Cancer Lett 2016; 381: 370-379
[13] Yan F, Qian M, He Q, Zhu H, Yang B. The posttranslational modifications of Hippo-YAP pathway in cancer. Biochim Biophys Acta Gen Subj 2020; 1864:129397
[14] Qian M, Yan F, Yuan T, Yang B, He Q, Zhu H. Targeting post-translational modification of transcription factors as cancer therapy. Drug Discov Today 2020; 25: 1502-1512
[15] Deng L, Meng T, Chen L, Wei W, Wang P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal Transduct Target Ther 2020; 5:11
[16] Schauer NJ, Magin RS, Liu X, Doherty LM, Buhrlage SJ. Advances in discovering deubiquitinating enzyme (DUB) inhibitors. J Med Chem 2020; 63: 2731-2750
[17] Bushweller JH. Targeting transcription factors in cancer-from undruggable to reality. Nat Rev Cancer 2019; 19: 611-624
[18] Chen XX, Yin Y, Cheng JW, Huang A, Hu B, Zhang X, et al. BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways. Cell Death Dis 2018; 9:1036
[19] Artegiani B, van Voorthuijsen L, Lindeboom RGH, Seinstra D, Heo I, Tapia P, et al. Probing the tumor suppressor function of BAP1 in CRISPR-engineered human liver organoids. Cell Stem Cell 2019; 24: 927-943
[20] Yuan M, Chen X, Sun Y, Jiang L, Xia Z, Ye K, et al. ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression. Acta Pharm Sin B 2020; 10: 1426-1439
[21] Zhu H, Yan F, Yuan T, Qian M, Zhou T, Dai X, et al. USP10 promotes proliferation of hepatocellular carcinoma by deubiquitinating and stabilizing YAP/TAZ. Cancer Res 2020; 80: 2204-2216
[22] Sugihara T, Werneburg NW, Hernandez MC, Yang L, Kabashima A, Hirsova P, et al. YAP tyrosine phosphorylation and nuclear localization in cholangiocarcinoma cells are regulated by LCK and independent of LATS Activity. Mol Cancer Res 2018; 16: 1556-1567
[23] D’Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther 2015; 147: 32-54
[24] Seki T, Gong L, Williams AJ, Sakai N, Todi SV, Paulson HL. JosD1, a membrane-targeted deubiquitinating enzyme, is activated by ubiquitination and regulates membrane dynamics, cell motility, and endocytosis. J Biol Chem 2013; 288: 17145-17155
[25] Zhang B, Zheng A, Hydbring P, Ambroise G, Ouchida AT, Goiny M, et al. PHGDH defines a metabolic subtype in lung adenocarcinomas with poor prognosis. Cell Rep 2017; 19: 2289-2303
[26] Krassikova L, Zhang B, Nagarajan D, Queiroz AL, Kacal M, Samakidis E, et al. The deubiquitinase JOSD2 is a positive regulator of glucose metabolism. Cell Death Differ 2020; 28: 1091-1109
[27] Zhou L, Liu T, Huang B, Luo M, Chen Z, Zhao Z, et al. Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development. J Allergy Clin Immunol 2020; 147: 267-279
[28] Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015; 15: 73-79
[29] Zhu C, Ji X, Zhang H, Zhou Q, Cao X, Tang M, et al. Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway. J Biol Chem 2018; 293: 1178-1191
[30] Toloczko A, Guo F, Yuen H-F, Wen Q, Wood SA, Ong YS, et al. Deubiquitinating enzyme USP9X suppresses tumor growth via LATS kinase and core components of the Hippo pathway. Cancer Res 2017; 77: 4921-4933
[31] Kim Y, Kim W, Song Y, Kim JR, Cho K, Moon H, et al. Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability. Proc Natl Acad Sci U S A 2017; 114: 4691-4696
[32] Zhang Z, Du J, Wang S, Shao L, Jin K, Li F, et al. OTUB2 promotes cancer metastasis via Hippo-independent activation of YAP and TAZ. Mol Cell 2019; 73: 7-21
[33] Pan B, Yang Y, Li J, Wang Y, Fang C, Yu FX, et al. USP47-mediated deubiquitination and stabilization of YAP contributes to the progression of colorectal cancer. Protein Cell 2020; 11: 138-143
[34] O’Rourke CJ, Munoz-Garrido P, Andersen JB. Molecular targets in cholangiocarcinoma. Hepatology 2020; 73: 62-74
[35] Pei T, Li Y, Wang J, Wang H, Liang Y, Shi H, et al. YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 2015; 6: 17206-17220
[36] Reggiani F, Gobbi G, Ciarrocchi A, Sancisi V. YAP and TAZ are not identical twins. Trends Biochem Sci 2021; 46: 154-168
[37] Noguchi S, Saito A, Horie M, Mikami Y, Suzuki HI, Morishita Y, et al. An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer. Clin Cancer Res 2014; 20: 4660-4672
[38] Hayashi H, Higashi T, Yokoyama N, Kaida T, Sakamoto K, Fukushima Y, et al. An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression. Cancer Res 2015; 75: 4985-4997
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