Abstract 3088: Regulation of tight junction protein claudin 1 mRNA expression by AU-rich element-binding (ELAV) proteins in colon cancer

Abstract

Abstract Tight junction associated proteins are key molecular components governing cellular adhesion, polarity and play critical roles in cellular proliferation via their functions as couplers of the extracellular milieu to intracellular signaling pathways. Claudin-1, a tight junction protein, expression is dysregulated in the majority of human colorectal carcinomas. We have previously reported that claudin-1 is regulated at post-transcriptional levels on treatment with HDAC inhibitor, TSA and its mRNA stability is modulated by 3’-UTR as the major mechanism underlying HDAC-dependent claudin-1 expression. It has putative AU-rich (ARE) cis-elements in its long 3’UTR (∼ 2.3Kb). Presence of a long 3’UTR is frequently indicative of post-translational regulation of gene expression via modulation of mRNA stability. ELAV like RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) associate with labile mRNAs bearing AU-rich elements located in the 3’ untranslated regions (3′-UTRs) and modulate their stability. We have identified putative AU rich elements in the proximal region of the claudin 1 3’-UTR and demonstrate that HuR interacts with these AU-rich elements. We further show a role of HuR and TTP during colon tumorigenesis and their ability to regulate Claudin-1 mRNA expression in presence TSA. We found that Claudin-1 mRNA was stabilized by HUR in both SW480 and SW620 cells, whereas its overexpression decreased the expression of TTP; We used a ribonomic approach to test the binding of HuR and TTP to claudin 1 3’UTR and their role in stabilization/destabilization of claudin-1 mRNA in the presence of TSA. On treatment with TSA the binding of HuR to claudin-1 3’UTR decreases while the binding of TTP increases correlating well with the rapid decay of claudin-1 mRNA in presence of TSA. Thus, our data suggest that claudin 1 is regulated via mRNA stability and a novel regulatory feedback loop between HuR and TTP in colon tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3088. doi:10.1158/1538-7445.AM2011-3088