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

Oncogene volume 29, pages 305–312 (2010)Cite this article

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.

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Acknowledgements

This work was supported by NIH grant CA119005, CA124977 (P Dhawan), and AHA Grant 0435471N, 5P50DK044757 and P30DK058406 Pilot project (AB Singh), the Society of University Surgeons-Ethicon Scholarship Award (JJS) CA112215 (TJ Yeatman), DK052334, CA 069457, the GI Cancer SPORE grant CA95103 (RD Beauchamp), the Vanderbilt-Ingram Cancer Center P30CA68485 and the NIH grant supporting the Digestive Diseases Center DK58404. We thank Christian Kis for the help in real-time quantitative reverse transcription–PCR analysis.

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Authors and Affiliations

  1. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

    M Krishnan, A B Singh, J J Smith, A Sharma, R D Beauchamp & P Dhawan

  2. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    J J Smith & R D Beauchamp

  3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    X Chen

  4. H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    S Eschrich & T J Yeatman

  5. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    R D Beauchamp & P Dhawan

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  1. M Krishnan
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  2. A B Singh
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  3. J J Smith
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  4. A Sharma
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  5. X Chen
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  6. S Eschrich
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  7. T J Yeatman
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  8. R D Beauchamp
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  9. P Dhawan
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Correspondence to P Dhawan.

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Krishnan, M., Singh, A., Smith, J. et al. HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability. Oncogene 29, 305–312 (2010). https://doi.org/10.1038/onc.2009.324

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