title: Suberoylanilide hydroxamic acid (SAHA)-induced dynamics of a human histone deacetylase protein interaction network.
abstract: Histone deacetylases (HDACs) are targets for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. We then assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2's association with the complex. Our dynamic protein interaction network resource provides novel insights into the molecular mechanism of SAHA action and demonstrates the potential for drugs to rewire networks.
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Mihaela E
authors: ME
authors: Sardiu
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Karen T
authors: KT
authors: Smith
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Brad D
authors: BD
authors: Groppe
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Joshua M
authors: JM
authors: Gilmore
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Anita
authors: A
authors: Saraf
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Rhonda
authors: R
authors: Egidy
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Allison
authors: A
authors: Peak
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Chris W
authors: CW
authors: Seidel
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Laurence
authors: L
authors: Florens
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110;
authors: Jerry L
authors: JL
authors: Workman
authors: From the ‡Stowers Institute for Medical Research, Kansas City, Missouri 64110; ¶Department of Pathology and Laboratory Medicine, the University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, Kansas 66160 mpw@stowers.org.
authors: Michael P
authors: MP
authors: Washburn
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011485:Protein Binding; D060066:Protein Interaction Maps; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D056264:Sin3 Histone Deacetylase and Corepressor Complex / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000077337:Vorinostat
chemical_list: 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; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex