Cancer epigenetics.
Aberrant DNA methylation of the promoter region is a key mechanism for inactivation of genes that suppress tumorigenesis. Genes that are involved in every step of tumor formation can be silenced by this mechanism. Inhibitors of DNA methylation, such as 5-azadeoxycytidine (5AZA), can reverse this epigenetic event suggesting a potential use in cancer therapy. The structure of chromatin can also play an important role with respect to the regulation of gene expression. Chromatin containing hypoacetylated lysines in histones has a compact structure that is repressive for transcription. Inhibitors of histone deacetylase (HDAC) can convert chromatin to an open structure and activate certain genes that inhibit tumor growth. These HDAC inhibitors also have potential in cancer therapy. A 'cross-talk' between DNA methylation and histone deacetylation can occur and work in concert to silence gene expression. The molecular mechanism involves the attachment of a methylated CpG binding protein (MBP) to the methylated promoters and its recruitment of HDAC to form a complex that suppresses transcription. These two epigenetic modifications represent an interesting target for therapeutic intervention using 5AZA and HDAC inhibitors. These agents in combination have been shown to produce a synergistic reactivation of tumor suppressor genes and an enhanced antineoplastic effect against tumor cells, and should be investigated as a novel form of epigenetic therapy for cancer.
Momparler
Richard L
RL
Département de pharmacology, Université de Montréal, Centre de recherché, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine Montreal, Que H3T 1C5, Canada. richard.l.momparler@umontreal.ca
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000628:therapy
D020533:Angiogenesis Inhibitors; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases