Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer

作者: Elizabeth E. Cameron , Kurtis E. Bachman , Sanna Myöhänen , James G. Herman , Stephen B. Baylin

DOI: 10.1038/5047

关键词:

摘要: Densely methylated DNA associates with transcriptionally repressive chromatin characterized by the presence of underacetylated histones1,2. Recently, these two epigenetic processes have been dynamically linked. The methyl-CpG-binding protein MeCP2 appears to reside in a complex histone deacetylase activity3,4. can mediate formation on promoter templates vitro, and this process be reversed trichostatin A (TSA), specific inhibitor deacetylase3,4,5. Little is known, however, about relative roles methylation activity stable inhibition transcription densely endogenous promoters, such as those for silenced alleles imprinted genes6, genes female inactive X chromosome7 tumour-suppressor inactivated cancer cells8,9. We show here that hypermethylated MLH1, TIMP3 (TIMP-3), CDKN2B (INK4B, p15) CDKN2A (INK4, p16) cannot reactivated TSA alone tumour cells which we shown upregulate expression non-methylated genes. Following minimal demethylation slight gene reactivation low dose 5-aza-2´deoxycytidine (5Aza-dC), treatment results robust re-expression each gene. does not contribute genes, none treatments alter structure associated promoters. Thus, although deacetylation appear act synergistic layers silencing cancer, dense CpG island dominant maintenance silent state at loci.

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