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

Oncogene. 2010 Jan 14;29(2):305-12. doi: 10.1038/onc.2009.324. Epub 2009 Nov 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Butyrates / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Claudin-1
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Immunoblotting
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • RNA Interference
  • RNA Stability / drug effects*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic / drug effects


  • 3' Untranslated Regions
  • Butyrates
  • CLDN1 protein, human
  • Claudin-1
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Membrane Proteins
  • RNA, Messenger
  • trichostatin A
  • HDAC2 protein, human
  • Histone Deacetylase 2