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Review
. 2015 Jul 1;23(1):66-84.
doi: 10.1089/ars.2014.5863. Epub 2014 Mar 27.

Mechanisms of Histone Deacetylase Inhibitor-Regulated Gene Expression in Cancer Cells

Anderly C Chueh  1 , Janson W T Tse  1 , Lars Tögel  1 , John M Mariadason  1
Affiliations
Review

Mechanisms of Histone Deacetylase Inhibitor-Regulated Gene Expression in Cancer Cells

Anderly C Chueh et al. Antioxid Redox Signal. .

Abstract

Significance: Class I and II histone deacetylase inhibitors (HDACis) are approved for the treatment of cutaneous T-cell lymphoma and are undergoing clinical trials as single agents, and in combination, for other hematological and solid tumors. Understanding their mechanisms of action is essential for their more effective clinical use, and broadening their clinical potential.

Recent advances: HDACi induce extensive transcriptional changes in tumor cells by activating and repressing similar numbers of genes. These transcriptional changes mediate, at least in part, HDACi-mediated growth inhibition, apoptosis, and differentiation. Here, we highlight two fundamental mechanisms by which HDACi regulate gene expression—histone and transcription factor acetylation. We also review the transcriptional responses invoked by HDACi, and compare these effects within and across tumor types.

Critical issues: The mechanistic basis for how HDACi activate, and in particular repress gene expression, is not well understood. In addition, whether subsets of genes are reproducibly regulated by these agents both within and across tumor types has not been systematically addressed. A detailed understanding of the transcriptional changes elicited by HDACi in various tumor types, and the mechanistic basis for these effects, may provide insights into the specificity of these drugs for transformed cells and specific tumor types.

Future directions: Understanding the mechanisms by which HDACi regulate gene expression and an appreciation of their transcriptional targets could facilitate the ongoing clinical development of these emerging therapeutics. In particular, this knowledge could inform the design of rational drug combinations involving HDACi, and facilitate the identification of mechanism-based biomarkers of response.

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Figures

<b>FIG. 1.</b>
FIG. 1.
HDACi regulate gene expression through histone and transcription factor hyperacetylation. HDACi, histone deacetylase inhibitor. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 2.</b>
FIG. 2.
Mechanisms by which HDACi-induced histone acetylation may alter higher-order chromatin structure. (A, B) Charge neutralization. Acetylation of positively charged lysine residues on histone tails (black circles) reduces affinity for (A) negatively charged phosphate groups (PO4−) on DNA in adjacent histones, or (B) the negatively charged region on the surface of H2A-H2B (dark blue oval), causing histones to become less compacted. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 3.</b>
FIG. 3.
HDACi-induced histone hyper-acetylation may impact transcription through altered binding of bromodomain-containing proteins. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 4.</b>
FIG. 4.
Specific histone lysine residues acetylated by HDACi. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 5.</b>
FIG. 5.
Transcription factors acetylated by HDACi. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 6.</b>
FIG. 6.
Extent of overlap in gene expression change mediated by HDACi in two colon cancer cell lines. Genes induced or repressed by twofold or greater were included in the analysis. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 7.</b>
FIG. 7.
Model of HDACi-mediated transcriptional activation at GC rich, Sp1/Sp3-regulated promoters. Sp, specificity protein. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
<b>FIG. 8.</b>
FIG. 8.
Model of HDACi-mediated transcriptional repression at GC-rich, Sp1/Sp3-regulated promoters. Top panel represents the basal state, and bottom panel represents the HDACi-treated state. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars
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References

    1. Agricola E, Randall RA, Gaarenstroom T, Dupont S, and Hill CS. Recruitment of TIF1gamma to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol Cell 43: 85–96, 2011 - PubMed
    1. Allfrey VG. Post-synthetic modifications of histone structure: a mechanism for the control of chromosome structure by the modulation of histone-DNA interactions. In: Chromatin and Chromosome Structure, edited by Li HJ. and Eckhardt RE. New York: Academic, 1977, pp. 167–191
    1. Allfrey VG, Faulkner R, and Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci U S A 51: 786–794, 1964 - PMC - PubMed
    1. Amin MR, Dudeja PK, Ramaswamy K, and Malakooti J. Involvement of Sp1 and Sp3 in differential regulation of human NHE3 promoter activity by sodium butyrate and IFN-gamma/TNF-alpha. Am J Physiol Gastrointest Liver Physiol 293: G374–G382, 2007 - PubMed
    1. Ammanamanchi S, Freeman JW, and Brattain MG. Acetylated sp3 is a transcriptional activator. J Biol Chem 278: 35775–35780, 2003 - PubMed

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