Abstract 1895: Metastasis-associated protein 1 drives prostate cancer progression and metastasis through regulation of onco-epimicroRNAs

Abstract

Abstract Our recent studies in prostate-specific tumor suppressor Pten gene compromised transgenic mice, revealed a strategic role for Metastasis Associated protein 1 (MTA1), a component of the chromatin remodeling NuRD complex and a key regulator of metastasis, in the progression of prostate cancer. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) analyses from the mouse prostate tissues showed MTA1 occupancy of several potential oncogenic miRNA target promoters including miR-22. Retrospective investigation of microRNA microarray experiments revealed downregulation of these candidate miRNAs in LNCaP cells silenced for MTA1 expression (shMTA1). Real time PCR evaluation of shMTA1 cell lines, LNCaP, DU145 and PC3M attested the microarray findings. Using miRNA-mRNA target prediction algorithms, miRanda, miRDB and Targetscan, E-cadherin (CDH1) was identified as a potential target with high context score for miR-22. Interestingly, E-cadherin, which has a pivotal role in preventing Epithelial to Mesenchymal Transition (EMT) of tumor cells was also identified as a MTA1 target gene by ChIP-Seq analysis. Further, qRT-PCR and western blot experiments validated that MTA1 levels had an inverse correlation with E-cadherin expression in these cell lines. Transient transfection of miR-22 mimics diminished E-cadherin levels while this expression was restored by miR-22 sponge inhibitors showing that miR-22 can control E-cadherin expression. Ongoing experiments aim to address the direct targeting of E-cadherin 3′UTR by miR-22 using Dual-Glo luciferase reporter assay and the functional consequences of miR-22 promoter regulation by MTA1 utilizing chromatin and RNA immunoprecipitation assays. Our studies reveal a novel and previously unrecognized role for MTA1-mediated miR-22 regulation of E-cadherin. Citation Format: Swati Dhar, Nasir A. Butt, Avinash Kumar, Xu Zhang, Anait S. Levenson. Metastasis-associated protein 1 drives prostate cancer progression and metastasis through regulation of onco-epimicroRNAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1895.