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

Krishnan M, Singh AB, Smith JJ, Sharma A, Chen X, Eschrich S, Yeatman TJ, Beauchamp RD, Dhawan P
Oncogene. 2010 29 (2): 305-12

PMID: 19881542 · PMCID: PMC3388773 · DOI:10.1038/onc.2009.324

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.

MeSH Terms (18)

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

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