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 c...
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description | 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.
► HDACi dissociate the PHD finger protein ING2 from the Sin3 deacetylase complex ► Chromatin binding of the Sin3 complex is disrupted by HDACi through loss of ING2 |
doi_str_mv | 10.1016/j.chembiol.2009.12.010 |
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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.
► HDACi dissociate the PHD finger protein ING2 from the Sin3 deacetylase complex ► Chromatin binding of the Sin3 complex is disrupted by HDACi through loss of ING2</description><identifier>ISSN: 1074-5521</identifier><identifier>EISSN: 1879-1301</identifier><identifier>DOI: 10.1016/j.chembiol.2009.12.010</identifier><identifier>PMID: 20142042</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Cell Line ; CELLBIO ; CHEMBIO ; DNA ; Histone Deacetylase Inhibitors - pharmacology ; Homeodomain Proteins - metabolism ; Humans ; Hydroxamic Acids - pharmacology ; Promoter Regions, Genetic - drug effects ; ras Proteins - genetics ; Receptors, Cytoplasmic and Nuclear - metabolism ; Sin3 Histone Deacetylase and Corepressor Complex - metabolism ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Chemistry & biology, 2010-01, Vol.17 (1), p.65-74</ispartof><rights>2010 Elsevier Ltd</rights><rights>Copyright (c) 2010 Elsevier Ltd. All rights reserved.</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-93f72961f7a4210e95e46980e3993cd924467e9f4f35dbdb85024711a53b621e3</citedby><cites>FETCH-LOGICAL-c470t-93f72961f7a4210e95e46980e3993cd924467e9f4f35dbdb85024711a53b621e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.chembiol.2009.12.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20142042$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smith, Karen T.</creatorcontrib><creatorcontrib>Martin-Brown, Skylar A.</creatorcontrib><creatorcontrib>Florens, Laurence</creatorcontrib><creatorcontrib>Washburn, Michael P.</creatorcontrib><creatorcontrib>Workman, Jerry L.</creatorcontrib><title>Deacetylase Inhibitors Dissociate the Histone-Targeting ING2 Subunit from the Sin3 Complex</title><title>Chemistry & biology</title><addtitle>Chem Biol</addtitle><description>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.
► HDACi dissociate the PHD finger protein ING2 from the Sin3 deacetylase complex ► Chromatin binding of the Sin3 complex is disrupted by HDACi through loss of ING2</description><subject>Cell Line</subject><subject>CELLBIO</subject><subject>CHEMBIO</subject><subject>DNA</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>ras Proteins - genetics</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Sin3 Histone Deacetylase and Corepressor Complex - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1O3DAQxy3UqtClr7DKCyTMOM6HL6jVboGVUHuAXrhYjjPZ9SqJV7YXlbcnsF1ET5xmpPl_aH6MzREyBCwvtpnZ0NBY12ccQGbIM0A4YWdYVzLFHPDTtEMl0qLgeMq-hrAFAKxl-YWdckDBQfAz9rAkbSg-9TpQsho3trHR-ZAsbQjOWB0piRtKbmyIbqT0Xvs1RTuuk9Wva57c7Zv9aGPSeTe86u7smCcLN-x6-nvOPne6D_Tt35yxP1c_7xc36e3v69Xix21qRAUxlXlXcVliV2nBEUgWJEpZA-VS5qaVXIiyItmJLi_apm3qArioEHWRNyVHymfs8pC72zcDtYbG6HWvdt4O2j8pp636_zLajVq7R8VrlLLGKaA8BBjvQvDUvXkR1AtttVVH2uqFtkKuJtqTcf6--c12xDsJvh8ENP3_aMmrYCyNhlrryUTVOvtRxzMtiZTJ</recordid><startdate>20100129</startdate><enddate>20100129</enddate><creator>Smith, Karen T.</creator><creator>Martin-Brown, Skylar A.</creator><creator>Florens, Laurence</creator><creator>Washburn, Michael P.</creator><creator>Workman, Jerry L.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20100129</creationdate><title>Deacetylase Inhibitors Dissociate the Histone-Targeting ING2 Subunit from the Sin3 Complex</title><author>Smith, Karen T. ; Martin-Brown, Skylar A. ; Florens, Laurence ; Washburn, Michael P. ; Workman, Jerry L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-93f72961f7a4210e95e46980e3993cd924467e9f4f35dbdb85024711a53b621e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Cell Line</topic><topic>CELLBIO</topic><topic>CHEMBIO</topic><topic>DNA</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Promoter Regions, Genetic - drug effects</topic><topic>ras Proteins - genetics</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Sin3 Histone Deacetylase and Corepressor Complex - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Smith, Karen T.</creatorcontrib><creatorcontrib>Martin-Brown, Skylar A.</creatorcontrib><creatorcontrib>Florens, Laurence</creatorcontrib><creatorcontrib>Washburn, Michael P.</creatorcontrib><creatorcontrib>Workman, Jerry L.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemistry & biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Karen T.</au><au>Martin-Brown, Skylar A.</au><au>Florens, Laurence</au><au>Washburn, Michael P.</au><au>Workman, Jerry L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deacetylase Inhibitors Dissociate the Histone-Targeting ING2 Subunit from the Sin3 Complex</atitle><jtitle>Chemistry & biology</jtitle><addtitle>Chem Biol</addtitle><date>2010-01-29</date><risdate>2010</risdate><volume>17</volume><issue>1</issue><spage>65</spage><epage>74</epage><pages>65-74</pages><issn>1074-5521</issn><eissn>1879-1301</eissn><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.
► HDACi dissociate the PHD finger protein ING2 from the Sin3 deacetylase complex ► Chromatin binding of the Sin3 complex is disrupted by HDACi through loss of ING2</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>20142042</pmid><doi>10.1016/j.chembiol.2009.12.010</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Cell Line CELLBIO CHEMBIO DNA Histone Deacetylase Inhibitors - pharmacology Homeodomain Proteins - metabolism Humans Hydroxamic Acids - pharmacology Promoter Regions, Genetic - drug effects ras Proteins - genetics Receptors, Cytoplasmic and Nuclear - metabolism Sin3 Histone Deacetylase and Corepressor Complex - metabolism Tumor Suppressor Proteins - metabolism |
title | Deacetylase Inhibitors Dissociate the Histone-Targeting ING2 Subunit from the Sin3 Complex |
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