Trichostatin-A modulates claudin-1 mRNA stability through the modulation of Hu antigen R and tristetraprolin in colon cancer cells.

Sharma A, Bhat AA, Krishnan M, Singh AB, Dhawan P
Carcinogenesis. 2013 34 (11): 2610-21

PMID: 23880304 · PMCID: PMC3810835 · DOI:10.1093/carcin/bgt207

Expression of claudin-1, a tight junction protein, is highly upregulated in colon cancer. We have reported that claudin-1 expression in colon cancer cells is epigenetically regulated as histone deacetylase (HDAC) inhibitors decrease claudin-1 messenger RNA (mRNA) stability and thus expression. In this regard, our data suggested a role of the 3'-untranslated region (UTR) in the regulation of HDAC-dependent regulation of claudin-1 mRNA stability. In the current study, we demonstrate, based on our continued investigation, that the ELAV-like RNA-binding proteins (RBPs), human antigen R (HuR) and tristetraprolin (TTP) associate with the 3'-UTR of claudin-1 mRNA to modulate the latter's stability. Ribonomic and site-directed mutagenesis approaches were used to confirm the binding of HuR and TTP to the 3'-UTR of claudin-1. We further confirmed their roles in the stabilization of claudin-1 mRNA, under conditions of HDAC inhibition. In summary, we report that HuR and TTP are the critical regulators of the posttranscriptional regulation of claudin-1 expression in colon cancer cells. We also demonstrate that inhibition of HDACs by trichostatin treatment decreased the binding of HuR while increasing the binding of TTP to the 3'-UTR of claudin-1. Additionally, we provide data showing transcriptional regulation of claudin-1 expression, through the regulation of transcription factor Sp1. Taken together, we demonstrate epigenetic regulation of claudin-1 expression in colon cancer cells at the transcriptional and posttranscriptional levels.

MeSH Terms (24)

3' Untranslated Regions Base Sequence Blotting, Western Breast Neoplasms Cells, Cultured Chromatin Immunoprecipitation Claudin-1 Colonic Neoplasms ELAV Proteins Epigenesis, Genetic Female Fluorescent Antibody Technique Gene Expression Regulation, Neoplastic Histone Deacetylase Inhibitors Humans Hydroxamic Acids Immunoenzyme Techniques Kidney Molecular Sequence Data Mutagenesis, Site-Directed Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Tristetraprolin

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