Histone modification enzymes: novel targets for cancer drugs.
In eukaryotes, genomic DNA is packaged with histone proteins into the cell nucleus as chromatin, condensing the DNA > 10,000-fold. Chromatin is highly dynamic and exerts profound control on gene expression. Localised chromatin decondensation facilitates access of nuclear machinery. Chromatin displays epigenetic inheritance, in that changes in its structure can pass to the next generation independently of the DNA sequence itself. It is now clear that the post-translational modification of histones, for example, acetylation, methylation and phosphorylation, plays a crucial role in the regulation of nuclear function through the 'histone code'. There has been significant progress in identifying and understanding the enzymes that control these complex processes, in particular histone acetyltransferases and histone deacetylases. The exciting discovery that compounds inhibiting histone deacetylase activity also have antitumour properties has focused attention on their use as anticancer drugs. As a consequence, there is ongoing evaluation of several histone deacetylase inhibitor compounds in Phase I and II clinical trials with promising early results. It is likely that many of the enzymes involved in the control of histone modification will provide therapeutic opportunities for the treatment of cancer, including histone methyltransferases and Aurora kinases.
Kristeleit
Rebecca
R
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
Stimson
Lindsay
L
Workman
Paul
P
Aherne
Wynne
W
D000107:Acetylation / Q000187:drug effects; D000123:Acetyltransferases / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D002986:Clinical Trials as Topic; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000187:drug effects*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000187:drug effects*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D006656:Protamine Kinase / Q000187:drug effects*; D011496:Protein Methyltransferases; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases
D000970:Antineoplastic Agents; D002843:Chromatin; D006657:Histones; D009363:Neoplasm Proteins; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006656:Protamine Kinase; D017027:Protein Tyrosine Phosphatases; D006655:Histone Deacetylases