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Molecular Cancer
Published in: Molecular Cancer 1/2008

Open Access 01-12-2008 | Research

Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells

Authors: Marielle Dejligbjerg, Morten Grauslund, Thomas Litman, Laura Collins, Xiaozhong Qian, Michael Jeffers, Henri Lichenstein, Peter Buhl Jensen, Maxwell Sehested

Published in: Molecular Cancer | Issue 1/2008

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Abstract

Background

Histone acetylation is an epigenetic modification involved in the regulation of gene expression, balanced by histone acetyl transferases and histone deacetylase (HDAC) enzymes. HDAC inhibitors (HDACi) induce growth arrest and cell death in transformed cells, and are currently in many clinical cancer trials. The transcriptional response to HDACi is complex, as is the response to HDAC isoform knockdown (KD). Here, we describe for the first time in a human cancer cell line, a transcriptional comparison of treatment by two structurally unrelated HDACi; belinostat and valproic acid with the KD of HDAC1, 2 and 3 isoforms.

Results

HDAC KD showed anti-proliferative effects, although to a lesser extent than HDACi treatment. Moreover, we found a 2-fold increased resistance of HDAC1 knockdown cells to belinostat, suggesting this isoenzyme as a selective target. While both HDACi treatment and individual class I HDAC KD produce significant transcriptional effects, three-times higher for HDACi, the gene-expression profiles of class I HDAC KD compared with that obtained by HDACi treatment exhibited less than 4% of altered genes in common between the two modes of inhibition. Further, cell-specific effects of HDAC KD are evident by comparison with a recent study in a different cell line.

Conclusion

The increased resistance to belinostat in response to HDAC1 depletion indicates the possibility of using this isoform as a predictive biomarker of response to HDACi treatment. Further, the transcriptional response to chemical inhibition of HDACs is very different from that of KD of individual class I HDAC isoforms. These data suggest that the anti-tumor effect of HDACi is indeed linked to class I inhibition, but may be more complex than simply targeting individual HDAC enzymes.
Appendix
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Metadata
Title
Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells
Authors
Marielle Dejligbjerg
Morten Grauslund
Thomas Litman
Laura Collins
Xiaozhong Qian
Michael Jeffers
Henri Lichenstein
Peter Buhl Jensen
Maxwell Sehested
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2008
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-7-70

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