title: Trichostatin-A modulates claudin-1 mRNA stability through the modulation of Hu antigen R and tristetraprolin in colon cancer cells.
abstract: 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.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, MCN, B-2211, Nashville, TN 37232, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.forename: Ajaz A
authors.initials: AA
authors.lastname: Bhat
authors.forename: Moorthy
authors.initials: M
authors.lastname: Krishnan
authors.forename: Amar B
authors.initials: AB
authors.lastname: Singh
authors.forename: Punita
authors.initials: P
authors.lastname: Dhawan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D062445:Claudin-1 / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D062445:Claudin-1; D051959:ELAV Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D051816:Tristetraprolin; C012589:trichostatin A