CONICET | Buscador de Institutos y Recursos Humanos

Epidemiologic studies demonstrated that metabolic syndrome (MeS)increased prostate cancer (PCa) risk and aggressiveness. Our previousstudies showed that MeS and the C-terminalbinding protein 1 (CtBP1)cooperate to induce PCa growth in mice. Genome-wide expression profiles andGene Set Enrichment Analysis (GSEA) from these tumors, identified to chloride channel accessory 2 (CLCA2) as a key CtBP1-repressed gene. CLCA2 wasdescribed as a tumor suppressor gene that links cell adhesion to cytosolicsignaling proteins implicated in breast cancer EMT. We also found that CtBP1associates to CLCA2 promoter and represses its expression in vivo and in vitro. Thegoal of this work was to understand the biological relevance and the molecularmechanisms whereby the transcriptional co-regulator CtBP1 represses CLCA2. PC3cells were co-transfected with CtBP1, the promoter CLCA2 reporter plasmid and the Zn Finger E-boxbinding homeobox 1 (ZEB1), p65 or different histone deacetylases (HDACs)expression plasmids. We found that CLCA2 promoter activity was not modulated byp65, whereas ZEB1, HDAC2 or HDAC3 together with CtBP1 synergistically repressedCLCA2 promoter activity. Moreover, the HDAC inhibitor (TSA) significantlyincreased CLCA2 promoter activity and expression. We hybridized a miRNAexpression microarray from PCa xenografts growth in MeS mice. Afternormalization and bioinformatic data analysis, we found several miRNAs thattarget CLCA2. Among them, the CtBP1-induced hsa-miR-196b, stands out for itsrole in oral and gastric cancer cell invasion. Thus, we assessed miR196b/CLCA2 rolein cell adhesion. miR-196b overexpression decreased PC3 cell adhesion, while CLCA2promoted cell adhesion in these cells. In turn, CLCA2 depletion dramaticallydecreased cell adhesion. In summary, this study describes for the first timethat CLCA2 is epigenetically regulated by HDACs, ZEB1, miR-196b and CtBP1 in PCacells modulating PCa cell adhesion.