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Issue 983 coverEPIGENETICS IN CANCER PREVENTION: EARLY DETECTION AND RISK ASSESSMENT Copyright © 2003 by the New York Academy of Sciences
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Articles by PONTE, J. F.
Annals of the New York Academy of Sciences 983:84-100 (2003)
© 2003 New York Academy of Sciences

Histone Deacetylases: Unique Players in Shaping the Epigenetic Histone Code

SAM THIAGALINGAMa,b,c, KUANG-HUNG CHENGc, HYUNJOO J. LEEa, NORA MINEVAc, ARUNTHATHI THIAGALINGAMd AND JOSE F. PONTEa

aGenetics and Molecular Medicine Programs and Pulmonary Center, Department of Medicine, bDepartment of Genetics and Genomics, and cDepartment of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA
dBayer Corporation, 333 Coney Street, East Walpole, Massachusetts 02032, USA

Address for correspondence: Sam Thiagalingam, Genetics Program, Boston University School of Medicine, 715 Albany Street, L320, Boston, MA 02118. Voice: 617-638-6013; fax: 617-638-4275.
samthia{at}bu.edu
Ann. N.Y. Acad. Sci. 983: 84-100 (2003).

The epigenome is defined by DNA methylation patterns and the associated posttranslational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The silencing of gene expression is associated with deacetylated histones, which are often found to be associated with regions of DNA methylation as well as methylation at the lysine 4 residue of histone 3. In contrast, the activation of gene expression is associated with acetylated histones and methylation at the lysine 9 residue of histone 3. The histone deactylases play a major role in keeping the balance between the acetylated and deacetylated states of chromatin. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are similar to the yeast RPD3 protein and localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are homologous to the yeast HDA1 protein and are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are similar to the yeast SIR2 proteins. Since inappropriate silencing of critical genes can result in one or both hits of tumor suppressor gene (TSG) inactivation in cancer, theoretically the reactivation of affected TSGs could have an enormous therapeutic value in preventing and treating cancer. Indeed, several HDAC inhibitors are currently being developed and tested for their potency in cancer chemotherapy. Importantly, these agents are also potentially applicable to chemoprevention if their toxicity can be minimized. Despite the toxic side effects and lack of specificity of some of the inhibitors, progress is being made. With the elucidation of the structures, functions and modes of action of HDACs, finding agents that may be targeted to specific HDACs and potentially reactivate expression of only a defined set of affected genes in cancer will be more attainable.

Key Words: histone deacetylases (HDAC) • histone code • active histone code (AHC) • silenced histone code (SHC) • histone deacetylase inhibitor (HDACi) • cancer therapy




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