1. Academic Validation
  2. HDACs class II-selective inhibition alters nuclear receptor-dependent differentiation

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

  • J Mol Endocrinol. 2010 Oct;45(4):219-28. doi: 10.1677/JME-10-0043.
Angela Nebbioso 1 Carmela Dell'Aversana Anne Bugge Roberta Sarno Sergio Valente Dante Rotili Fabio Manzo Diana Teti Susanne Mandrup Paolo Ciana Adriana Maggi Antonello Mai Hinrich Gronemeyer Lucia Altucci
Affiliations

Affiliation

  • 1 Dipartimento di Patologia Generale, Seconda Università di Napoli, Naples, Italy.
Abstract

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 Peroxisome Proliferator-activated Receptor γ (PPARγ)-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 PPARγ-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 PPARγ signaling mostly in the heart and adipose tissues. These results illustrate how HDAC functions can be dissected by selective inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16914
    HDAC抑制剂