Deacetylase inhibitors dissociate the histone-targeting ING2 subunit from the Sin3 complex.
Histone deacetylase (HDAC) inhibitors are in clinical development for several diseases, including cancers and neurodegenerative disorders. HDACs 1 and 2 are among the targets of these inhibitors and are part of multisubunit protein complexes. HDAC inhibitors (HDACis) block the activity of HDACs by chelating a zinc molecule in their catalytic sites. It is not known if the inhibitors have any additional functional effects on the multisubunit HDAC complexes. Here, we find that suberoylanilide hydroxamic acid (SAHA), the first FDA-approved HDACi for cancer, causes the dissociation of the PHD-finger-containing ING2 subunit from the Sin3 deacetylase complex. Loss of ING2 disrupts the in vivo binding of the Sin3 complex to the p21 promoter, an important target gene for cell growth inhibition by SAHA. Our findings reveal a molecular mechanism by which HDAC inhibitors disrupt deacetylase function.
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Karen T
KT
Smith
Skylar A
SA
Martin-Brown
Laurence
L
Florens
Michael P
MP
Washburn
Jerry L
JL
Workman
D002460:Cell Line; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000077337:Vorinostat; D018631:ras Proteins / Q000235:genetics
D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; C444654:ING2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; D000077337:Vorinostat; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D018631:ras Proteins