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    Chem Biol. 2010 Jan 29;17(1):65-74.

    Deacetylase inhibitors dissociate the histone-targeting ING2 subunit from the Sin3 complex.

    Smith KT, Martin-Brown SA, Florens L, Washburn MP, Workman JL.

    Source

    Stowers Institute for Medical Research, Kansas City, MO 64110, USA.

    Abstract

    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.

    Copyright (c) 2010 Elsevier Ltd. All rights reserved.

    PMID:
    20142042
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC2819981
    Free PMC Article

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