HDACs class II-selective inhibition alters nuclear receptor-dependent differentiation

Epigenetic deregulation contributes to diseases including cancer, neurodegeneration, osteodystrophy, cardiovascular defects and obesity. For this reason, several inhibitors for histone deacetylases (HDACs) are being validated as novel anti-cancer drugs in clinical studies and display important anti-proliferative activities. While most inhibitors act on both class I, II and IV HDACs, evidence is accumulating that class I is directly involved in regulation of cell growth and death, whereas class II members regulate differentiation processes, such as muscle- and neuronal differentiation. Here we show that the novel class II-selective inhibitor MC1568 interferes with the RAR and PPAR-mediated differentiation-inducing signaling pathways. In F9 cells this inhibitor specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells MC1568 attenuates PPAR–induced adipogenesis, while the class I-selective MS275 blocked adipogenesis completely thus revealing a different mode of action and/or target profile of the two classes of HDACs. Using in vivo reporting PPRE-luc mice we find that MC1568 impairs PPAR signaling mostly in the heart and adipose tissues. Thes