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ZEB1 Collaborates with ELK3 to Repress E-Cadherin Expression in Triple Negative Breast Cancer Cells

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ZEB1 Collaborates with ELK3 to Repress E-Cadherin Expression in Triple Negative Breast Cancer Cells Author Manuscript Published OnlineFirst on September 11, 2019; DOI: 10.1158/1541-7786.MCR-19-0380 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ZEB1 collaborates with ELK3 to repress E-cadherin expression in triple negative breast cancer cells Hyeon-Ju Cho1,†, Nuri Oh1, †, Ji-Hoon Park1, †, Kwang-Soo Kim, Hyung-Keun Kim1, Eunbyeol Lee1, Sohyun Hwang1, Seong-Jin Kim2, Kyung-Soon Park1,* 1Department of Biomedical Science, College of Life Science, CHA University, 620, CHA Biocomplex, Sampyeong-Dong, Bundang-gu, Seongnam-si, 13488, Republic of Korea 2Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Republic of Korea †These authors contributed equally to this work. *Corresponding author: E-mail address: [email protected] (Kyung-Soon Park) Running title: ZEB1 and ELK3 complex targets E-cadherin in breast cancer Disclosure of Potential Conflicts of Interest The authors declare no potential conflicts of interest. 1 Downloaded from mcr.aacrjournals.org on October 8, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 11, 2019; DOI: 10.1158/1541-7786.MCR-19-0380 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract ZEB1 has intrinsic oncogenic functions that control the epithelial-to-mesenchymal transition (EMT) of cancer cells, impacting tumorigenesis from its earliest stages. By integrating microenvironment signals and being implicated in feedback regulatory loops, ZEB1 appears to be a central switch that determines EMT and metastasis of cancer cells. Here, we found that ZEB1 collaborates with ELK3, a ternary complex factor belonging to the ETS family, to repress E-cadherin expression. ZEB1 functions as a transcriptional activator of ELK3. We first identified that ELK3 and ZEB1 have a positively correlated expression in breast cancer cells by using multiple databases for correlation analysis. Molecular analysis revealed that ZEB1 functions as a transcriptional activator of ELK3 expression. GST pull-down assay and coimmunoprecipitation analysis of wild-type or domain deletion mutants of ZEB1 and ELK3 showed that these two proteins directly bound each other. Furthermore, we demonstrated that ZEB1 and ELK3 collaborate to repress the expression of E-cadherin, a representative protein that initiates EMT. Our finding suggested that ELK3 is a novel factor of the ZEB1/E- cadherin axis in triple negative breast cancer cells. Implications: ELK3 is a novel factor in the ZEB1/E-cadherin axis and ZEB1 has a dual role in ELK3 as a transcriptional activator and as a collaborator to repress E-cadherin expression in triple negative breast cancer cells. Keywords: ZEB1, ELK3, E-cadherin, transcriptional repressor complex Abbreviations: EMT, epithelial-to-mesenchymal transition; CIP, CtBP interaction domain; SID, Smad interaction domain; CBD, p300-P/CAF binding domain; Co-IP, coimmunoprecipitation; CID, C-terminal inhibitory domain; NID, N-terminal inhibitory domain. 2 Downloaded from mcr.aacrjournals.org on October 8, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 11, 2019; DOI: 10.1158/1541-7786.MCR-19-0380 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Epithelial-to-mesenchymal transition (EMT) results in the transition of epithelial cells to a mesenchymal phenotype that is defined by the change in the expression of prototypical markers such as E-cadherin and vimentin. EMT was first described in embryonic development and has been demonstrated to play a crucial role in cancer cells by inducing aberrant motility, dissemination and metastasis (1,2). EMT is executed by EMT-inducible transcription factors, mainly of the SNAIL, SLUG, TWIST and ZEB families (3). Regarding EMT-inducible transcription factors, ZEB1 has been demonstrated to be a particularly potent factor that is associated with aggressive behavior, metastasis and poor clinical prognosis in various tumor types, including pancreatic, lung and breast cancer (4-6). ZEB1 contains two zinc finger clusters that are responsible for binding to specific DNA sequences called E-box elements (7). In addition, ZEB1 contains several protein binding domains, including the CtBP interaction domain (CID), Smad interaction domain (SID) and p300-P/CAF binding domain (CBD) (7-9). By recruiting corepressors or coactivators through these domains, ZEB1 can either suppress or activate the expression of its target genes (9,10). For instance, ZEB1 functions as a transcriptional repressor of E-cadherin (10) by directly binding to the E-box located in the promoter of E-cadherin and recruiting the CtBP transcriptional cosuppressors (11) and/or the SWI/SNF chromatin-remodeling protein BRG1 (12). On the other hand, the direct binding of ZEB1 to YAP enhances the transcriptional expression of a subset of YAP target genes, converting ZEB1 from a transcription inhibitor into a transcription activator; this conversion is a strong predictor of poor clinical outcome in hormone receptor-negative breast cancer (13). Although there is accumulating evidence that ZEB1 is a pivotal factor in inducing EMT and metastasis of cancer in vitro and in vivo, a recent report revealed that ZEB1 knockout resulted in an incomplete inhibition of the metastatic ability of colorectal cancers, suggesting that there are additional factors that collaborate with ZEB1 to complete the phenotypic changes related to metastasis (14). ELK3, a ternary complex factor belonging to the ETS family of transcription factors, is associated with various cellular phenomena such as wound healing, lymphangiogenesis and vasculogenesis both in vitro and in vivo (15-17). In addition, the findings of multiple studies support the link between ELK3 and cancer metastasis (18-20). Suppression of ELK3 decreases migration and invasion ability of basal like breast cancer cells in vitro (21). In vivo 3 Downloaded from mcr.aacrjournals.org on October 8, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 11, 2019; DOI: 10.1158/1541-7786.MCR-19-0380 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. studies show that a depletion of ELK3 leads to the formation of smaller tumors due to the inability of the tumor to become vascularized and oxygenated (17). In aggressive triple- negative (ER-, PR-, HER2-) breast cancer, ELK3 orchestrates metastasis through several distinct mechanisms, including the regulation of GATA3 expression, the production of VEGFC and the expression of cell-to-cell adhesion-related genes (18,22,23). The regulation of ELK3 activity is determined by a comprehensive regulatory signaling network, which is described as follows. First, having two transcriptional repressor domains at the N- and C- termini, ELK3 usually functions as a strong transcriptional repressor (24); however, ELK3 is transformed into a transcriptional activator when it is phosphorylated by Ras/ERK signaling (25). Second, ELK3 can be shuttled between the nucleus and cytoplasm depending on intracellular signaling, and nuclear ELK3 can be exported into the cytoplasm in response to stress-activated kinases, in particular JNK (26). For these reasons, despite the pleiotropic activity of ELK3 in both developmental and pathological progression, the underlying mechanism of ELK3 in regulating the expression of downstream target genes is poorly understood. Recent studies suggest that ELK3 promotes liver fibrosis by regulating the EMT process (27). This result makes it feasible to speculate that the regulatory axis of ELK3 is in line with that of ZEB1 during the EMT process. If so, the linkage between ELK3 and ZEB1 activity could provide useful information to understand tumor metastasis as well as EMT. Here, we specifically test the hypothesis that ELK3 and ZEB1 collaborate with each other to endow the mesenchymal characteristics of MDA-MB-231; these characteristics constitute a critical phenotype of the cells for aggressive metastatic behavior. Using multiple databases for correlation analysis, we first explored the possibility that the expression of ELK3 and ZEB1 are closely related to breast cancer cells. We performed comprehensive molecular and cellular analyses and showed that ZEB1 is a direct transcriptional activator that contributes to the regulation of ELK3 expression. We also revealed that ELK3 and ZEB1 form transcriptional repressor complexes through direct protein-to-protein interactions. More importantly, we demonstrated that ELK3 is another partner of ZEB1 that represses the expression of E-cadherin, a representative protein that initiates EMT. 4 Downloaded from mcr.aacrjournals.org on October 8, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 11, 2019; DOI: 10.1158/1541-7786.MCR-19-0380 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Materials and methods Plasmids, siRNA and primers Information on the plasmids and sequences used for primers and siRNAs is indicated in the supplementary information section, as shown in Table S1 and Table S2. Cell culture and transfection The human embryonic kidney 293T cell line was used for the coimmunoprecipitation (co-IP) assay and expression of various genes. The well-known triple-negative breast cancer cell line
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