Cyclic Tetrapeptides Bearing a Sulfhydryl Group Potently Inhibit Histone Deacety

The reversible acetylation of -amino groups of lysine residues clustered near the amino terminus of nucleosomal histones by histone deacetylases (HDACs) and histone acetyl transferases (HATs) has a significant influence o­n the chromatin superstructure and o­n the interactions of DNA with transcriptional regulators. Modification of the level of histone acetylation and its consequences have received enormous interest in recent years, and increasing evidence supports their importance for basic cellular functions such as DNA replication, transcription, differentiation, and apoptosis. Aberrant histone acetylation emerging from HAT mutations or abnormal recruitment of HDACs has been correlated with carcinogenesis. Inappropriate recruitment of HDACs provides a common molecular mechanism by which genes necessary for proper differentiation or growth suppression can be silenced, leading to excessive proliferation. It is therefore proposed that HDACs are a potential target for the development of a small-molecule anticancer agent.

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