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 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.
Nebbioso
Angela
A
Dipartimento di Patologia Generale, Seconda Università di Napoli, Naples, Italy.
Dell'Aversana
Carmela
C
Bugge
Anne
A
Sarno
Roberta
R
Valente
Sergio
S
Rotili
Dante
D
Manzo
Fabio
F
Teti
Diana
D
Mandrup
Susanne
S
Ciana
Paolo
P
Maggi
Adriana
A
Mai
Antonello
A
Gronemeyer
Hinrich
H
Altucci
Lucia
L
D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D014212:Tretinoin; D006655:Histone Deacetylases