Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability
Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed ma...
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| Veröffentlicht in: | Oncotarget 2016-01, Vol.7 (2), p.1796-1807 |
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| creator | Chao, Min-Wu Chu, Po-Chen Chuang, Hsiao-Ching Shen, Fang-Hsiu Chou, Chih-Chien Hsu, En-Chi Himmel, Lauren E Huang, Han-Li Tu, Huang-Ju Kulp, Samuel K Teng, Che-Ming Chen, Ching-Shih |
| description | Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNA-mediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer. |
| doi_str_mv | 10.18632/oncotarget.6427 |
| format | Article |
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The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNA-mediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.6427</identifier><identifier>PMID: 26625202</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Blotting, Western ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Depsipeptides - pharmacology ; Epigenesis, Genetic ; Female ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - genetics ; Histone Deacetylases - metabolism ; Humans ; MCF-7 Cells ; Mice, Inbred NOD ; Mice, SCID ; Microscopy, Confocal ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Nylons - pharmacology ; Phenylbutyrates - pharmacology ; Protein Stability ; Pyrroles - pharmacology ; Receptor, Notch1 - genetics ; Receptor, Notch1 - metabolism ; Repressor Proteins - antagonists & inhibitors ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Research Paper ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - metabolism ; Transplantation, Heterologous</subject><ispartof>Oncotarget, 2016-01, Vol.7 (2), p.1796-1807</ispartof><rights>Copyright: © 2016 Chao et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-d234fc1f4eb8037b68bb0e0323ab168886e604cbb05b7be9d083b6a149f6a0b93</citedby><cites>FETCH-LOGICAL-c354t-d234fc1f4eb8037b68bb0e0323ab168886e604cbb05b7be9d083b6a149f6a0b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811498/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811498/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27911,27912,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26625202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chao, Min-Wu</creatorcontrib><creatorcontrib>Chu, Po-Chen</creatorcontrib><creatorcontrib>Chuang, Hsiao-Ching</creatorcontrib><creatorcontrib>Shen, Fang-Hsiu</creatorcontrib><creatorcontrib>Chou, Chih-Chien</creatorcontrib><creatorcontrib>Hsu, En-Chi</creatorcontrib><creatorcontrib>Himmel, Lauren E</creatorcontrib><creatorcontrib>Huang, Han-Li</creatorcontrib><creatorcontrib>Tu, Huang-Ju</creatorcontrib><creatorcontrib>Kulp, Samuel K</creatorcontrib><creatorcontrib>Teng, Che-Ming</creatorcontrib><creatorcontrib>Chen, Ching-Shih</creatorcontrib><title>Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNA-mediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Depsipeptides - pharmacology</subject><subject>Epigenesis, Genetic</subject><subject>Female</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - metabolism</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Microscopy, Confocal</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Nylons - pharmacology</subject><subject>Phenylbutyrates - pharmacology</subject><subject>Protein Stability</subject><subject>Pyrroles - pharmacology</subject><subject>Receptor, Notch1 - genetics</subject><subject>Receptor, Notch1 - metabolism</subject><subject>Repressor Proteins - antagonists & inhibitors</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Research Paper</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - metabolism</subject><subject>Transplantation, Heterologous</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1rGzEQhkVoqUPqe09Bx1w21ddqtZeCcfMFIb20ZyHJs2uVXcmVtAH_-6zr1E0GxAyadx5peBH6Qsk1VZKzrzG4WEzqoVxLwZozdE5b0VasrvmHN_UCLXP-TeaoRaNY-wktmJSsZoSdo_gUQwU730OA4h3upuCKjwHHDt9_X60V9gEn6KfBFB96bBOYXLAzwUHCucCIHQxDxnaPR-NDmc9B9xSL21K8S7HATMjFWD_4sv-MPnZmyLB8zRfo1-3Nz_V99fjj7mG9eqwcr0WpNoyLztFOgFWEN1YqawkQzrixVCqlJEgi3HxZ28ZCuyGKW2moaDtpiG35Bfp25O4mO8LGQSjJDHqX_GjSXkfj9ftO8Fvdx2ctFJ0pagZcvQJS_DNBLnr0-bCqCRCnrGkj65bKVvBZSo5Sl2LOCbrTM5Tov1bp_1bpg1XzyOXb750G_hnDXwAYtJSs</recordid><startdate>20160112</startdate><enddate>20160112</enddate><creator>Chao, Min-Wu</creator><creator>Chu, Po-Chen</creator><creator>Chuang, Hsiao-Ching</creator><creator>Shen, Fang-Hsiu</creator><creator>Chou, Chih-Chien</creator><creator>Hsu, En-Chi</creator><creator>Himmel, Lauren E</creator><creator>Huang, Han-Li</creator><creator>Tu, Huang-Ju</creator><creator>Kulp, Samuel K</creator><creator>Teng, Che-Ming</creator><creator>Chen, Ching-Shih</creator><general>Impact Journals LLC</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160112</creationdate><title>Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability</title><author>Chao, Min-Wu ; Chu, Po-Chen ; Chuang, Hsiao-Ching ; Shen, Fang-Hsiu ; Chou, Chih-Chien ; Hsu, En-Chi ; Himmel, Lauren E ; Huang, Han-Li ; Tu, Huang-Ju ; Kulp, Samuel K ; Teng, Che-Ming ; Chen, Ching-Shih</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-d234fc1f4eb8037b68bb0e0323ab168886e604cbb05b7be9d083b6a149f6a0b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Blotting, Western</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Depsipeptides - pharmacology</topic><topic>Epigenesis, Genetic</topic><topic>Female</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - genetics</topic><topic>Histone Deacetylases - metabolism</topic><topic>Humans</topic><topic>MCF-7 Cells</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Microscopy, Confocal</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Nylons - pharmacology</topic><topic>Phenylbutyrates - pharmacology</topic><topic>Protein Stability</topic><topic>Pyrroles - pharmacology</topic><topic>Receptor, Notch1 - genetics</topic><topic>Receptor, Notch1 - metabolism</topic><topic>Repressor Proteins - antagonists & inhibitors</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Research Paper</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>Spheroids, Cellular - drug effects</topic><topic>Spheroids, Cellular - metabolism</topic><topic>Transplantation, Heterologous</topic><toplevel>online_resources</toplevel><creatorcontrib>Chao, Min-Wu</creatorcontrib><creatorcontrib>Chu, Po-Chen</creatorcontrib><creatorcontrib>Chuang, Hsiao-Ching</creatorcontrib><creatorcontrib>Shen, Fang-Hsiu</creatorcontrib><creatorcontrib>Chou, Chih-Chien</creatorcontrib><creatorcontrib>Hsu, En-Chi</creatorcontrib><creatorcontrib>Himmel, Lauren E</creatorcontrib><creatorcontrib>Huang, Han-Li</creatorcontrib><creatorcontrib>Tu, Huang-Ju</creatorcontrib><creatorcontrib>Kulp, Samuel K</creatorcontrib><creatorcontrib>Teng, Che-Ming</creatorcontrib><creatorcontrib>Chen, Ching-Shih</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chao, Min-Wu</au><au>Chu, Po-Chen</au><au>Chuang, Hsiao-Ching</au><au>Shen, Fang-Hsiu</au><au>Chou, Chih-Chien</au><au>Hsu, En-Chi</au><au>Himmel, Lauren E</au><au>Huang, Han-Li</au><au>Tu, Huang-Ju</au><au>Kulp, Samuel K</au><au>Teng, Che-Ming</au><au>Chen, Ching-Shih</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-01-12</date><risdate>2016</risdate><volume>7</volume><issue>2</issue><spage>1796</spage><epage>1807</epage><pages>1796-1807</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNA-mediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26625202</pmid><doi>10.18632/oncotarget.6427</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Blotting, Western Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Depsipeptides - pharmacology Epigenesis, Genetic Female Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - genetics Histone Deacetylases - metabolism Humans MCF-7 Cells Mice, Inbred NOD Mice, SCID Microscopy, Confocal Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Nylons - pharmacology Phenylbutyrates - pharmacology Protein Stability Pyrroles - pharmacology Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Repressor Proteins - antagonists & inhibitors Repressor Proteins - genetics Repressor Proteins - metabolism Research Paper Reverse Transcriptase Polymerase Chain Reaction RNA Interference Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism Transplantation, Heterologous |
| title | Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability |
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