Upregulation of USP11 promotes epithelial‑to‑mesenchymal transition by deubiquitinating Snail in ovarian cancer

Wang,Weiwei; Wang,Jing; Yan,Hua; Zhang,Kai; Liu,Yang

doi:10.3892/or.2018.6924

Upregulation of USP11 promotes epithelial‑to‑mesenchymal transition by deubiquitinating Snail in ovarian cancer

Authors:
- Weiwei Wang
- Jing Wang
- Hua Yan
- Kai Zhang
- Yang Liu
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Affiliations: Department of Obstetrics, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China, Department of Orthopaedics, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
Published online on: December 12, 2018 https://doi.org/10.3892/or.2018.6924
Pages: 1739-1748

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Abstract

Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme (DUB) and has been observed to promote mammary tumor initiation and progression. Several reports have shown that USP11 plays an important role in cancer development. Previous research has shown that USP11 is upregulated in breast cancer, but the function of USP11 in ovarian cancer has not been determined to date. In the present study, we observed that USP11 was upregulated in ovarian cancer tissues and cell lines. To determine the role of USP11 in ovarian cancer, we performed several functional experiments, including Transwell migration and invasion analysis, in vitro and in vivo deubiquitination assays, colony formation assays, and CCK‑8 assays. Notably, we observed that USP11 facilitated the epithelial‑to‑mesenchymal transition (EMT), which is an important process in cancer cell invasion and metastasis. Furthermore, we observed that USP11 regulated EMT through the regulation of Snail. Our results revealed that USP11 promoted EMT in ovarian cancer by deubiquitinating Snail, and USP11 may be a novel therapeutic target for ovarian cancer treatment.

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1	Skaar JR, Pagan JK and Pagano M: SCF ubiquitin ligase-targeted therapies. Nat Rev Drug Discov. 13:889–903. 2014. View Article : Google Scholar : PubMed/NCBI
2	Lipkowitz S and Weissman AM: RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer. 11:629–643. 2011. View Article : Google Scholar : PubMed/NCBI
3	Kim D, Hong A, Park HI, Shin WH, Yoo L, Jeon SJ and Chung KC: Deubiquitinating enzyme USP22 positively regulates c-Myc stability and tumorigenic activity in mammalian and breast cancer cells. J Cell Physiol. 232:3664–3676. 2017. View Article : Google Scholar : PubMed/NCBI
4	Zhang QX, Wang XC, Chen SP and Qin XT: Predictive value of deubiquitination enzymes USP37 in the prognosis of breast cancer. Zhonghua Yi Xue Za Zhi. 96:944–948. 2016.(In Chinese). PubMed/NCBI
5	Schoenfeld AR, Apgar S, Dolios G, Wang R and Aaronson SA: BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol Cell Biol. 24:7444–7455. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bayraktar S, Gutierrez Barrera AM, Liu D, Pusztai L, Litton J, Valero V, Hunt K, Hortobagyi GN, Wu Y, Symmans F, et al: USP-11 as a predictive and prognostic factor following neoadjuvant therapy in women with breast cancer. Cancer J. 19:10–17. 2013. View Article : Google Scholar : PubMed/NCBI
7	Kim MS, Yoo KJ, Kang I, Chung HM and Baek KH: A novel cysteine protease HeLa DUB-1 responsible for cleaving the ubiquitin in human ovarian cancer cells. Int J Oncol. 25:373–379. 2004.PubMed/NCBI
8	Ramakrishna S, Suresh B and Baek KH: The role of deubiquitinating enzymes in apoptosis. Cell Mol Life Sci. 68:15–26. 2011. View Article : Google Scholar : PubMed/NCBI
9	Wu HC, Lin YC, Liu CH, Chung HC, Wang YT, Lin YW, Ma HI, Tu PH, Lawler SE and Chen RH: USP11 regulates PML stability to control Notch-induced malignancy in brain tumours. Nat Commun. 5:32142014. View Article : Google Scholar : PubMed/NCBI
10	Sun W, Tan X, Shi Y, Xu G, Mao R, Gu X, Fan Y, Yu Y, Burlingame S, Zhang H, et al: USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal. 22:386–394. 2010. View Article : Google Scholar : PubMed/NCBI
11	Al-Salihi MA, Herhaus L, Macartney T and Sapkota GP: USP11 augments TGFbeta signalling by deubiquitylating ALK5. Open Biol. 2:1200632012. View Article : Google Scholar : PubMed/NCBI
12	Gupta GP and Massague J: Cancer metastasis: Building a framework. Cell. 127:679–695. 2006. View Article : Google Scholar : PubMed/NCBI
13	Brabletz T, Kalluri R, Nieto MA and Weinberg RA: EMT in cancer. Nat Rev Cancer. 18:128–134. 2018. View Article : Google Scholar : PubMed/NCBI
14	Peinado H, Olmeda D and Cano A: Snail, Zeb and bHLH factors in tumour progression: An alliance against the epithelial phenotype? Nat Rev Cancer. 7:415–428. 2007. View Article : Google Scholar : PubMed/NCBI
15	Nagaishi M, Nakata S, Ono Y, Hirata K, Tanaka Y, Suzuki K, Yokoo H and Hyodo A: Tumoral and stromal expression of Slug, ZEB1, and ZEB2 in brain metastasis. J Clin Neurosci. 46:124–128. 2017. View Article : Google Scholar : PubMed/NCBI
16	Grzegrzolka J, Biala M, Wojtyra P, Kobierzycki C, Olbromski M, Gomulkiewicz A, Piotrowska A, Rys J, Podhorska-Okolow M and Dziegiel P: Expression of EMT markers SLUG and TWIST in breast cancer. Anticancer Res. 35:3961–3968. 2015.PubMed/NCBI
17	Soule HD, Vazguez J, Long A, Albert S and Brennan M: A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst. 51:1409–1416. 1973. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Zhou Z, Luo A, Shrivastava I, He M, Huang Y, Bahar I, Liu Z and Wan Y: Regulation of XIAP turnover reveals a role for USP11 in promotion of tumorigenesis. EBioMedicine. 15:48–61. 2017. View Article : Google Scholar : PubMed/NCBI
20	Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A and Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117:927–939. 2004. View Article : Google Scholar : PubMed/NCBI
21	Zheng H and Kang Y: Multilayer control of the EMT master regulators. Oncogene. 33:1755–1763. 2014. View Article : Google Scholar : PubMed/NCBI
22	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
23	Vetter G, Le Bechec A, Muller J, Muller A, Moes M, Yatskou M, Al Tanoury Z, Poch O, Vallar L and Friederich E: Time-resolved analysis of transcriptional events during SNAI1-triggered epithelial to mesenchymal transition. Biochem Biophys Res Commun. 385:485–491. 2009. View Article : Google Scholar : PubMed/NCBI
24	Naber HP, Drabsch Y, Snaar-Jagalska BE, ten Dijke P, van Laar T, Snail and Slug: key regulators of TGF-β-induced EMT, are sufficient for the induction of single-cell invasion. Biochem Biophys Res Commun. 435:58–63. 2013. View Article : Google Scholar : PubMed/NCBI
25	Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD and Chodosh LA: The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 8:197–209. 2005. View Article : Google Scholar : PubMed/NCBI
26	Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J and Nieto MA: Correlation of snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 21:3241–3246. 2002. View Article : Google Scholar : PubMed/NCBI
27	Lim KH, Suresh B, Park JH, Kim YS, Ramakrishna S and Baek KH: Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth. Oncotarget. 7:14441–14457. 2016. View Article : Google Scholar : PubMed/NCBI
28	Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M and Hung MC: Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 6:931–940. 2004. View Article : Google Scholar : PubMed/NCBI
29	Hsu DS, Wang HJ, Tai SK, Chou CH, Hsieh CH, Chiu PH, Chen NJ and Yang MH: Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages. Cancer Cell. 26:534–548. 2014. View Article : Google Scholar : PubMed/NCBI
30	Gudey SK, Sundar R, Mu Y, Wallenius A, Zang G, Bergh A, Heldin CH and Landström M: TRAF6 stimulates the tumor-promoting effects of TGFβ type I receptor through polyubiquitination and activation of presenilin 1. Sci Signal. 7:ra22014. View Article : Google Scholar : PubMed/NCBI