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

Ashok Sharma, Ajaz Ahmad Bhat, Moorthy Krishnan, Amar B. Singh, Punita Dhawan

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 HDACdependent 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 sitedirected 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.

Original languageEnglish
Pages (from-to)2610-2621
Number of pages12
JournalCarcinogenesis
Volume34
Issue number11
DOIs
Publication statusPublished - 1 Nov 2013
Externally publishedYes

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trichostatin A
Tristetraprolin
ELAV Proteins
Claudin-1
RNA Stability
Colonic Neoplasms
Messenger RNA
3' Untranslated Regions
Antigens
Sp1 Transcription Factor
Tight Junction Proteins
Histone Deacetylase Inhibitors
Histone Deacetylases
RNA-Binding Proteins
Epigenomics
Mutagenesis

ASJC Scopus subject areas

  • Cancer Research

Cite this

Trichostatin-A modulates claudin-1 mRNA stability through the modulation of hu antigen R and tristetraprolin in colon cancer cells. / Sharma, Ashok; Bhat, Ajaz Ahmad; Krishnan, Moorthy; Singh, Amar B.; Dhawan, Punita.

In: Carcinogenesis, Vol. 34, No. 11, 01.11.2013, p. 2610-2621.

Research output: Contribution to journalArticle

Sharma, Ashok ; Bhat, Ajaz Ahmad ; Krishnan, Moorthy ; Singh, Amar B. ; Dhawan, Punita. / Trichostatin-A modulates claudin-1 mRNA stability through the modulation of hu antigen R and tristetraprolin in colon cancer cells. In: Carcinogenesis. 2013 ; Vol. 34, No. 11. pp. 2610-2621.
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