USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc

被引:48
作者
Ge, Jianchao [1 ]
Yu, Wandong [1 ]
Li, Junhong [1 ]
Ma, Hangbin [1 ]
Wang, Pengyu [1 ]
Zhou, Yinghao [1 ]
Wang, Yang [1 ]
Zhang, Jun [1 ]
Shi, Guowei [1 ]
机构
[1] Fudan Univ, Peoples Hosp Shanghai 5, Dept Urol, 801 Heqing Rd, Shanghai 200240, Peoples R China
基金
上海市自然科学基金;
关键词
USP16; C-Myc; Deubiquitinase; Prostate cancer; ANDROGEN RECEPTOR; N-MYC; GENE-EXPRESSION; TRANSCRIPTION; PROMOTES; CCDC6;
D O I
10.1186/s13046-021-01843-8
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background c-Myc, a well-established oncogene, plays an important role in the initiation and progression of various cancers, including prostate cancer. However, its mechanism in cancer cell remains largely unknown and whether there exist a deubiquitinase targeting c-Myc also remains elusive. Methods Bioinformatic analysis and shRNA screening methods were used to identify potential deubiquitinases that correlate with c-Myc gene signature. Cell proliferation and viability were measured by Cell-Counting-Kit 8 and colony formation assays. A mouse xenograft model of PC3 cells was established to confirm the function of USP16 in vivo. The interaction between USP16 and c-Myc protein was assessed by co-immunoprecipitation and protein co-localization assays. Immunohistochemistry staining was performed to detect the expression of USP16, Ki67, and c-Myc in xenograft tissues and clinical tumour tissues. Furthermore, the correlation between USP16 and c-Myc was confirmed by RNA sequencing. Results Functional analyses identified USP16, known as a deubiquitinase, was strongly correlated with the c-Myc gene signature. Depletion of USP16 was shown to significantly suppress the growth of PCa cells both in vitro and in vivo. Co-immunoprecipitation and ubiquitination assays confirmed that USP16 served as a novel deubiquitinase of c-Myc and overexpression of c-Myc significantly rescued the effects of USP16 disruption. Immunohistochemistry staining and RNA-seq tactics were further used to confirm the positive correlation between USP16 and c-Myc expression. Expression of USP16 in human PCa tissues was higher than that seen in normal prostate tissues and its high expression was found associated with poor prognosis. Conclusions USP16 serves as a novel deubiquitinase of c-Myc. Downregulation of USP16 markedly suppressed PCa cell growth both in vitro and in vivo. USP16 regulates PCa cell proliferation by deubiquitinating and stabilizing c-Myc, making it a potential therapeutic candidate for the treatment of PCa.
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页数:15
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共 48 条
[1]   Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer [J].
Asangani, Irfan A. ;
Dommeti, Vijaya L. ;
Wang, Xiaoju ;
Malik, Rohit ;
Cieslik, Marcin ;
Yang, Rendong ;
Escara-Wilke, June ;
Wilder-Romans, Kari ;
Dhanireddy, Sudheer ;
Engelke, Carl ;
Iyer, Mathew K. ;
Jing, Xiaojun ;
Wu, Yi-Mi ;
Cao, Xuhong ;
Qin, Zhaohui S. ;
Wang, Shaomeng ;
Feng, Felix Y. ;
Chinnaiyan, Arul M. .
NATURE, 2014, 510 (7504) :278-+
[2]   Prostate cancer [J].
Attard, Gerhardt ;
Parker, Chris ;
Eeles, Ros A. ;
Schroder, Fritz ;
Tomlins, Scott A. ;
Tannock, Ian ;
Drake, Charles G. ;
de Bono, Johann S. .
LANCET, 2016, 387 (10013) :70-82
[3]   MYC Is Activated by USP2a-Mediated Modulation of MicroRNAs in Prostate Cancer [J].
Benassi, Barbara ;
Flavin, Richard ;
Marchionni, Luigi ;
Zanata, Silvio ;
Pan, Yunfeng ;
Chowdhury, Dipanjan ;
Marani, Marina ;
Strano, Sabrina ;
Muti, Paola ;
Blandino, Giovanni ;
Loda, Massimo .
CANCER DISCOVERY, 2012, 2 (03) :236-247
[4]   Myc and cell cycle control [J].
Bretones, Gabriel ;
Dolores Delgado, M. ;
Leon, Javier .
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, 2015, 1849 (05) :506-516
[5]   Deubiquitinating Enzyme Usp12 Is a Novel Co-activator of the Androgen Receptor [J].
Burska, Urszula L. ;
Harle, Victoria J. ;
Coffey, Kelly ;
Darby, Steven ;
Ramsey, Hollie ;
O'Neill, Daniel ;
Logan, Ian R. ;
Gaughan, Luke ;
Robson, Craig N. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (45) :32641-32650
[6]   Targeting oncogenic Myc as a strategy for cancer treatment [J].
Chen, Hui ;
Liu, Hudan ;
Qing, Guoliang .
SIGNAL TRANSDUCTION AND TARGETED THERAPY, 2018, 3
[7]   The Deubiquitinating Enzyme USP7 Regulates Androgen Receptor Activity by Modulating Its Binding to Chromatin [J].
Chen, Shu-Ting ;
Okada, Maiko ;
Nakato, Ryuichiro ;
Izumi, Kosuke ;
Bando, Masashige ;
Shirahige, Katsuhiko .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290 (35) :21713-21723
[8]   Identification of Novel Biomarkers of Homologous Recombination Defect in DNA Repair to Predict Sensitivity of Prostate Cancer Cells to PARP-Inhibitors [J].
Criscuolo, Daniela ;
Morra, Francesco ;
Giannella, Riccardo ;
Cerrato, Aniello ;
Celetti, Angela .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (12)
[9]   The c-Myc target gene network [J].
Dang, Chi V. ;
O'Donnell, Kathryn A. ;
Zeller, Karen I. ;
Nguyen, Tam ;
Osthus, Rebecca C. ;
Li, Feng .
SEMINARS IN CANCER BIOLOGY, 2006, 16 (04) :253-264
[10]   MYC on the Path to Cancer [J].
Dang, Chi V. .
CELL, 2012, 149 (01) :22-35