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Tgfβ-Activated USP27X Deubiquitinase Regulates Cell Migration And

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Tgfβ-Activated USP27X Deubiquitinase Regulates Cell Migration And Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 TGFβ-activated USP27X deubiquitinase regulates cell migration and 2 chemoresistance via stabilization of Snail1 3 4 Guillem Lambies1,2, Martina Miceli1, Catalina Martínez-Guillamon1, Rubén 5 Olivera-Salguero1, Raúl Peña1, Carolina-Paola Frías1, Irene Calderón1, Boyko S. 6 Atanassov3, Sharon Y. R. Dent4, Joaquín Arribas5,6,7, Antonio García de 7 Herreros1,2*, and Víctor M. Díaz1,2*. 8 1 9 Programa de Recerca en Càncer, Institut Hospital del Mar d’Investigacions Mèdiques 10 (IMIM), Unidad Asociada CSIC, Barcelona, Spain. 2 11 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra 12 (UPF), Barcelona, Spain. 3 13 Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer 14 Center, Buffalo, NY 15 4 Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer 16 Epigenetics, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 17 5 Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO) 18 CIBERONC, Barcelona, Spain 19 6 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain 20 7 Department of Biochemistry and Molecular Biology, Universitat Autònoma de 21 Barcelona, Campus de la UAB, Bellaterra, Spain 22 23 Running title: USP27X deubiquitinates Snail1 in tumor cells. 24 1 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 25 * Corresponding authors: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM) 26 and Universitat Pompeu Fabra (UPF), Parc de Recerca Biomèdica de Barcelona, Doctor 27 Aiguader, 88, E-08003, Barcelona, Spain; E-mails: [email protected]; 28 [email protected] 29 30 Keywords: EMT/ USP27X/ Deubiquitinase/ Snail1/ TGF/ invasion/ chemoresistance 31 Conflict of interest 32 The authors declare no conflicts of interest. 33 2 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 34 Abstract 35 In cancer cells, epithelial-to-mesenchymal transition (EMT) is controlled by Snail1, a 36 transcriptional factor also required for the activation of cancer-associated fibroblasts 37 (CAF). Snail1 is short-lived in normal epithelial cells as a consequence of its 38 coordinated and continuous ubiquitination by several F-box specific E3 ligases, but its 39 degradation is prevented in cancer cells and in activated fibroblasts. Here we performed 40 an siRNA screen and identified USP27X as a deubiquitinase that increases Snail1 41 stability. Expression of USP27X in breast and pancreatic cancer cell lines and tumors 42 positively correlated with Snail1 expression levels. Accordingly, downregulation of 43 USP27X decreased Snail1 protein in several tumor cell lines. USP27X depletion 44 impaired Snail1-dependent cell migration and invasion and metastasis formation and 45 increased cellular sensitivity to cisplatin. USP27X was upregulated by TGFβ during 46 EMT and was required for TGFβ-induced expression of Snail1 and other mesenchymal 47 markers in epithelial cells and CAF. In agreement with this, depletion of USP27X 48 prevented TGFβ-induced EMT and fibroblast activation. Collectively, these results 49 indicate that USP27X is an essential protein controlling Snail1 expression and function, 50 and may serve as a target for inhibition of Snail1-dependent tumoral invasion and 51 chemoresistance. 52 53 54 Significance 55 Findings show that inhibition of USP27X destabilizes Snail1 to impair EMT and 56 renders tumor cells sensitive to chemotherapy, thus opening new strategies for the 57 inhibition of Snail1 expression and its pro-tumoral actions. 3 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 58 Introduction 59 60 The epithelial-mesenchymal transition (EMT) is a reversible and highly conserved 61 biological process originally described during embryonic development that shifts 62 epithelial cells towards a mesenchymal phenotype (1). EMT is observed at the invasive 63 tumor front and correlates with enhanced invasiveness and poor clinical prognosis (2). 64 Phenotypically, tumor cells that have undergone an EMT become spindle-shaped and 65 motile and acquire new biological characteristics, such as a higher resistance to 66 chemotherapy (3,4). 67 68 EMT is defined by the down-regulation of the epithelial junctional protein E-Cadherin, 69 which is preceded by the expression of Snail1 repressor that directly binds to the E- 70 Cadherin gene (CDH1) promoter inhibiting its transcription (3). Snail1 also plays an 71 active role in the activation of mesenchymal genes, such as Fibronectin (3). Moreover, 72 Snail1 expression enhances resistance to apoptosis and the survival of tumor cells in 73 conditions of stress (3). For all these reasons Snail1 is considered a key protein 74 controlling EMT. 75 76 In accordance with its functions, Snail1 expression in human tumors is associated with 77 tumor progression, enhanced invasiveness and poor clinical prognosis (1). In pancreatic 78 cancer, carcinoma cells utilize an EMT program for metastatic dissemination (5). In 79 breast tumors, expression of Snail1 and other mesenchymal markers associates with 80 poor clinical parameters and to the particularly aggressive triple-negative breast cancer 81 (TNBC) subtype with a high rate of recurrence and distant metastasis (6). This suggests 82 that Snail1 is a possible target for therapeutic intervention. 4 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 83 Snail1 is a very unstable protein, tightly regulated by ubiquitination by several E3- 84 ubiquitin ligases that catalyze the transfer of ubiquitin (Ub) from the E2-conjugating 85 enzyme to a lysine residue in the substrate protein and the posterior elongation of the 86 Ub chains (7). Snail1 is targeted to the proteasome by several Skp-Culin-Fbox (SCF) E3 87 ligases (SCF-Fbxw1, SCF-Fbxl14, SCF-Fbxl5, SCF-FbxO11 and SCF-FbxO45) that 88 limit Snail1 expression in epithelial cells (8,9). Different reports have demonstrated the 89 stabilization of Snail1 with the concomitant down-regulation of Snail1 E3 ligases in 90 response to hypoxia, several pro-apoptotic insults such as -irradiation or antineoplastic 91 drugs (10-14). 92 93 Ubiquitination is a reversible process and the action of E3 ligases is antagonized by 94 deubiquitinating enzymes (DUBs) that recognize and remove Ub molecules (15). The 95 98 DUBs described so far are classified as cysteine proteases (Ub-specific proteases 96 (USP), Ub carboxy-terminal hydrolases (UCH), ovarian tumor-like proteases (OTU) or 97 "Machado-Joseph disease" proteases (MJD) and zinc metalloenzymes (the JAMM/MPN 98 class). The role of DUBs in cancer is stressed by the low stability exhibited by many 99 oncoproteins and the deregulation of their DUBs observed in tumors (16). 100 Despite the high number of E3 described targeting Snail1, only one DUB, DUB3 101 (USP17L2) has been recently shown to deubiquitinate Snail1 (17,18). In an effort to 102 identify new DUBs acting on Snail1 we have performed an siRNA screening on Snail1 103 expression in the MDA-MB-231 mammary cancer cell line and identified USP27X as a 104 DUB for Snail1. 105 5 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 106 Material and Methods 107 108 Cell culture, reagents, and antibodies. Authenticated cell lines were obtained from the 109 European Collection of Authenticated Cell Cultures (ECACC) or the American Type 110 Culture Collection (ATCC) and supplied by the Cancer Cell Line Repository from 111 IMIM. All cell lines were used for no more than 20 passages and routinely tested for 112 Mycoplasma contamination by PCR (19). The generation of murine embryonic 113 fibroblasts (MEFs) and cancer associated fibroblasts (CAFs) from MMTV-PyMT 114 tumors has been previously reported (20). Cells were maintained in DMEM (GIBCO- 115 BRL) with 10% heat inactivated FBS (GIBCO-BRL) at 37°C in 5% CO2. Where 116 indicated, cells were treated with 5 ng/mL of TGFβ1 (PeproTec), 10-100 μM of 117 cisplatin (Calbiochem), 20 M of the DUB inhibitor PR619 (LifeSensors), 20 µg/ml of 118 cycloheximide (Sigma-Aldrich) or 1 g/ml of doxycycline (Sigma-Aldrich). The 119 antibodies used in this work were: mouse monoclonal antibodies against Snail1 (21) and 120 Myc
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