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: Ashok Sharma, Ajaz A Bhat, Moorthy Krishnan, Amar B Singh, Punita Dhawan
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 11 Pg. 2610-21 (Nov 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23880304 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3' Untranslated Regions
• Claudin-1
• ELAV Proteins
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• RNA, Messenger
• Tristetraprolin
• trichostatin A

Topics

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