Histone deacetylases: Unique players in shaping the epigenetic histone code

被引:541
作者
Thiagalingam, S
Cheng, KH
Lee, HJ
Mineva, N
Thiagalingam, A
Ponte, JF
机构
[1] Boston Univ, Sch Med, Genet Program, Dept Med, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Program Mol Med, Dept Med, Boston, MA 02118 USA
[3] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA
[4] Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA
[5] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA
[6] Bayer Corp, East Walpole, MA 02032 USA
来源
EPIGENETICS IN CANCER PREVENTION: EARLY DETECTION AND RISK ASSESSMENT | 2003年 / 983卷
关键词
histone deacetylases (HDAC); histone code; active histone code (AHC); silenced histone code (SHC); histone deacetylase inhibitor (HDACi); cancer therapy;
D O I
10.1111/j.1749-6632.2003.tb05964.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 11 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.
引用
收藏
页码:84 / 100
页数:17
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