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Targeting Histone Deacetylase as a Strategy for Cancer Prevention

  • Ho Jung Oh
  • Eun Joo Chung
  • Sunmin Lee
  • Andrea Loaiza-Perez
  • Edward A. Sausville
  • Jane B. Trepel
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Histone proteins were identified in 1884 (1). For many years, the material that encoded genetic diversity was believed to consist of histones (2). Posttranslational modification of histones by acetylation, and detection of histone deacetylase (HDAC) activity (enzymatic removal of acetyl moieties from internal lysines in the N-terminal tails of core histones), was described more than 40 years ago (reviewed in 3), and more than 30 years ago, acetylation of histone tails was shown to be associated with transcriptionally active chromatin (4). However, in the past 10 years, interest in HDAC has increased dramatically, both as a key component of the transcription-regulatory apparatus and as a target for anticancer drug development. The Tetrahymena Gcn5 protein, which is highly homologous to the well-characterized yeast transcriptional activator Gcn5, was discovered to be a histone acetyltransferase (HAT), thus providing a mechanism for linking histone acetylation with transcriptional activation (5). Use of the HDAC inhibitor trapoxin in an affinity matrix to isolate and subsequently clone HDAC 1 (6) revealed the relationship between HDAC1 and the yeast transcriptional repressor RPD3, providing a link between histone deacetylation and transcriptional repression. Contemporaneously, molecular genetic studies of acute promyelocytic leukemia (APL) demonstrated that the gene-encoding retinoic acid receptor alpha (RARa) is involved in a reciprocal chromosomal translocation, producing oncogenic fusion proteins that aberrantly repress retinoic acid-responsive promoters and obstruct normal myeloid differentiation via inappropriate recruitment of HDAC to RARa-responsive promoters, thus associating deregulated HDAC activity and cancer (7).

Keywords

Acute Myeloid Leukemia Histone Deacetylase Acute Promyelocytic Leukemia HDAC Inhibitor Histone Deacetylase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Ho Jung Oh
  • Eun Joo Chung
  • Sunmin Lee
  • Andrea Loaiza-Perez
  • Edward A. Sausville
  • Jane B. Trepel

There are no affiliations available

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