Histone hyperacetylation induced by histone deacetylase inhibitors is not sufficient to cause growth inhibition in human dermal fibroblasts

Use of specific histone deacetylase inhibitors has revealed critical roles for the histone deacetylases (HDAC) in controlling proliferation. Although many studies have correlated the function of HDAC inhibitors with the hyper acetylation of histones, few studies have specifically addressed whether th e accumulation of acetylated histones, caused by HDAC inhibitor treatment, is responsible for growth inhibition. In the present study we show that HDA C inhibitors cause growth inhibition in normal and transformed keratinocyte s but not in normal dermal fibroblasts, This was despite the observation th at the HDAC inhibitor, suberic bishydroxamate (SBHA), caused a kinetically similar accumulation of hyperacetylated histones, This cell type-specific r esponse to SBHA was not due to the inactivation of SBHA by fibroblasts, nor was it due to differences in the expression of specific HDAC family member s. Remarkably, overexpression of HDACs 1, 4, and 6 in normal human fibrobla sts resulted in cells that could be growth-inhibited by SBHA. These data su ggest that, although histone acetylation is a major target for HDAC inhibit ors, the accumulation of hyperacetylated histones is not sufficient to caus e growth inhibition in all cell types, This suggests that growth inhibition , caused by HDAC inhibitors, may be the culmination of histone hyperacetyla tion acting in concert with other growth regulatory pathways.