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

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.

• Authors: M Krishnan, A B Singh, J J Smith, A Sharma, X Chen, S Eschrich, T J Yeatman, R D Beauchamp, P Dhawan
• Journal: Oncogene (Oncogene) Vol. 29 Issue 2 Pg. 305-12 (Jan 14 2010) ISSN: 1476-5594 [Electronic] England
• PMID: 19881542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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