HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability

M. Krishnan, A. B. Singh, J. J. Smith, A. Sharma, X. Chen, S. Eschrich, T. J. Yeatman, R. D. Beauchamp, P. Dhawan

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Expression and cellular distribution of claudin-1, a tight junction protein, is dysregulated in colon cancer and its overexpression in colon cancer cells induced dedifferentiation and increased invasion. However, the molecular mechanism(s) underlying dysregulated claudin-1 expression in colon cancer remains poorly understood. Histone deacetylase (HDAC)-dependent histone acetylation is an important mechanism of the regulation of cancer-related genes and inhibition of HDACs induces epithelial differentiation and decreased invasion. Therefore, in this study, we examined the role of HDAC-dependent epigenetic regulation of claudin-1 in colon cancer. In this study, we show that sodium butyrate and Trichostatin A (TSA), two structurally different and widely used HDAC inhibitors, inhibited claudin-1 expression in multiple colon cancer cell lines. Further studies revealed modulation of claudin-1 mRNA stability by its 3′-UTR as the major mechanism underlying HDAC-dependent claudin-1 expression. In addition, overexpression of claudin-1 abrogated the TSA-induced inhibition of invasion in colon cancer cells suggesting functional crosstalk. Analysis of mRNA expression in colon cancer patients, showed a similar pattern of increase in claudin-1 and HDAC-2 mRNA expression throughout all stages of colon cancer. Inhibition of claudin-1 expression by HDAC-2-specific small interfering RNA further supported the role of HDAC-2 in this regulation. Taken together, we report a novel post-transcriptional regulation of claudin-1 expression in colon cancer cells and further show a functional correlation between claudin-1 expression and TSA-mediated regulation of invasion. As HDAC inhibitors are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.

Original languageEnglish (US)
Pages (from-to)305-312
Number of pages8
JournalOncogene
Volume29
Issue number2
DOIs
StatePublished - Jan 2010

Keywords

  • Claudin-1
  • HDAC
  • Invasion
  • TSA
  • Tight junction

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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