Histone deacetylase inhibitors: Signalling towards p21cip1/waf1

Chromatin-modifying enzymes such as histone deacetylases (HDAC) facilitate a closed chromatin structure and hence transcriptional repression. HDAC are commonly affected in human cancer diseases. Thus, inhibition of HDAC represents a novel therapeutic approach. Several studies have shown that HDAC inhibitors strongly activate the expression of the cyclin-dependent kinase inhibitor p21cip1/waf1 through (i) enhanced histone acetylation around the p21cip1/waf1 promoter and (ii) the Sp1 sites on the p21cip1/waf1 promoter releasing the repressor HDAC1 from its binding. p21cip1/waf1 expression is regulated in a p53-dependent and p53-independent manner. The decision if p21cip1/waf1 up-regulation results in cell cycle arrest or apoptosis, decides about the therapeutic efficacy of an anti-cancer treatment with HDAC inhibitors.