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Inhibition of the deubiquitinase USP9x induces pre-B cell homeobox 1 (PBX1) degradation and thereby stimulates prostate cancer cell apoptosis.

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机构： [1]Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 511436, China, [2]Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China [3]Department of Urology, Nanjing Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 21002, China, the [4]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore, the [5]Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China, [6]Sichuan Kelun Pharmaceutical Co., Ltd., Chengdu, Sichuan 610071, China

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Chemoresistance is a leading obstacle in effective management of advanced prostate cancer (PCa). A better understanding of the molecular mechanisms involved in PCa chemoresistance could improve treatment of patients with PCa. In the present study, using immune histochemical, chemistry, and precipitation assays with cells from individuals with benign or malignant prostate cancer or established PCa cell lines, we found that the oncogenic transcription factor pre-B cell leukemia homeobox-1 (PBX1) promotes PCa cell proliferation and confers to resistance against common anti-cancer drugs such as doxorubicin and cisplatin. We observed that genetic PBX1 knockdown abrogates this resistance, and further experiments revealed that PBX1 stability was modulated by the ubiquitin-proteasomal pathway. To directly probe the impact of this pathway on PBX1 activity, we screened for PBX1-specific deubiquitinases (Dubs) and found that ubiquitin-specific peptidase 9 X-linked (USP9x) interacted with and stabilized the PBX1 protein by attenuating its Lys-48-linked polyubiquitination. Moreover, the USP9x inhibitor WP1130 markedly induced PBX1 degradation and promoted PCa cell apoptosis. The results in this study indicate that PBX1 confers to PCa chemoresistance and identify USP9x as a Dub of PBX1. We concluded that targeting the USP9x/PBX1 axis could be a potential therapeutic strategy for managing advanced prostate cancer. © 2019 Liu et al.

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出版当年[2019]版：

大类 | 2 区

生物学

小类 | 2 区生化与分子生物学

最新[2023]版：

大类 | 2 区

生物学

小类 | 2 区生化与分子生物学

第一作者：

第一作者机构： [1]Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 511436, China, [2]Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China [6]Sichuan Kelun Pharmaceutical Co., Ltd., Chengdu, Sichuan 610071, China

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通讯作者：

通讯机构： [1]Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 511436, China, [2]Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China [5]Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China, [*1]the First Affiliated Hospital of Soochow University, 188 Shizi St., Suzhou, Jiangsu 215006, China [*2]Key Lab of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou 511436, China

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