Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia
Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylas...
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| Veröffentlicht in: | The Journal of biological chemistry 2011-05, Vol.286 (18), p.16101-16108 |
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| container_title | The Journal of biological chemistry |
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| creator | Cenik, Basar Sephton, Chantelle F Dewey, Colleen M Xian, Xunde Wei, Shuguang Yu, Kimberley Niu, Wenze Coppola, Giovanni Coughlin, Sarah E Lee, Suzee E Dries, Daniel R Almeida, Sandra Geschwind, Daniel H Gao, Fen-Biao Miller, Bruce L Farese, Jr, Robert V Posner, Bruce A Yu, Gang Herz, Joachim |
| description | Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia. |
| doi_str_mv | 10.1074/jbc.M110.193433 |
| format | Article |
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By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.193433</identifier><identifier>PMID: 21454553</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Dose-Response Relationship, Drug ; Frontotemporal Dementia - drug therapy ; Frontotemporal Dementia - metabolism ; HEK293 Cells ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Hydroxamic Acids - pharmacology ; Intercellular Signaling Peptides and Proteins - biosynthesis ; Neurobiology ; Progranulins ; Transcription, Genetic - drug effects ; Up-Regulation - drug effects ; Vorinostat</subject><ispartof>The Journal of biological chemistry, 2011-05, Vol.286 (18), p.16101-16108</ispartof><rights>2011 by The American Society for Biochemistry and Molecular Biology, Inc. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091219/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091219/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21454553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cenik, Basar</creatorcontrib><creatorcontrib>Sephton, Chantelle F</creatorcontrib><creatorcontrib>Dewey, Colleen M</creatorcontrib><creatorcontrib>Xian, Xunde</creatorcontrib><creatorcontrib>Wei, Shuguang</creatorcontrib><creatorcontrib>Yu, Kimberley</creatorcontrib><creatorcontrib>Niu, Wenze</creatorcontrib><creatorcontrib>Coppola, Giovanni</creatorcontrib><creatorcontrib>Coughlin, Sarah E</creatorcontrib><creatorcontrib>Lee, Suzee E</creatorcontrib><creatorcontrib>Dries, Daniel R</creatorcontrib><creatorcontrib>Almeida, Sandra</creatorcontrib><creatorcontrib>Geschwind, Daniel H</creatorcontrib><creatorcontrib>Gao, Fen-Biao</creatorcontrib><creatorcontrib>Miller, Bruce L</creatorcontrib><creatorcontrib>Farese, Jr, Robert V</creatorcontrib><creatorcontrib>Posner, Bruce A</creatorcontrib><creatorcontrib>Yu, Gang</creatorcontrib><creatorcontrib>Herz, Joachim</creatorcontrib><title>Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia.</description><subject>Dose-Response Relationship, Drug</subject><subject>Frontotemporal Dementia - drug therapy</subject><subject>Frontotemporal Dementia - metabolism</subject><subject>HEK293 Cells</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Intercellular Signaling Peptides and Proteins - biosynthesis</subject><subject>Neurobiology</subject><subject>Progranulins</subject><subject>Transcription, Genetic - drug effects</subject><subject>Up-Regulation - drug effects</subject><subject>Vorinostat</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE1Lw0AQhhdRbK2evcke9RDdz7TxIEjxCyoeVPAWJrubdkuSXTabYn-E_9kEP9C5zDvMvM8Mg9AxJeeUTMXFulDnj3SoMi4430FjSmY84ZK-7aIxIYwmGZOzETpo2zXpQ2R0H40YFVJIycfo47krTHDbChpbWW3waquDe4faKgzKany6ccE2ro0Qz3Dnk2CWXQXRtNgHtwzQdJVtcOxFq4L10brmEgcYMlQ4rkwAb7o44HzvALXC0eEyuCa6aGrvQj-mTW2aaOEQ7ZVQteboO0_Q6-3Ny_w-WTzdPcyvF4lnqYwJUCYJEwKUSqFITVYyrTQrSmKmXMxKBpIJrVWvGc8yoadc8ZlIuUwFk5DxCbr64vquqI1W_fL-jNwHW0PY5g5s_r_T2FW-dJuck4wyOgBO_gJ-nT-P5Z84LoFl</recordid><startdate>20110506</startdate><enddate>20110506</enddate><creator>Cenik, Basar</creator><creator>Sephton, Chantelle F</creator><creator>Dewey, Colleen M</creator><creator>Xian, Xunde</creator><creator>Wei, Shuguang</creator><creator>Yu, Kimberley</creator><creator>Niu, Wenze</creator><creator>Coppola, Giovanni</creator><creator>Coughlin, Sarah E</creator><creator>Lee, Suzee E</creator><creator>Dries, Daniel R</creator><creator>Almeida, Sandra</creator><creator>Geschwind, Daniel H</creator><creator>Gao, Fen-Biao</creator><creator>Miller, Bruce L</creator><creator>Farese, Jr, Robert V</creator><creator>Posner, Bruce A</creator><creator>Yu, Gang</creator><creator>Herz, Joachim</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope></search><sort><creationdate>20110506</creationdate><title>Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia</title><author>Cenik, Basar ; Sephton, Chantelle F ; Dewey, Colleen M ; Xian, Xunde ; Wei, Shuguang ; Yu, Kimberley ; Niu, Wenze ; Coppola, Giovanni ; Coughlin, Sarah E ; Lee, Suzee E ; Dries, Daniel R ; Almeida, Sandra ; Geschwind, Daniel H ; Gao, Fen-Biao ; Miller, Bruce L ; Farese, Jr, Robert V ; Posner, Bruce A ; Yu, Gang ; Herz, Joachim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p265t-a1250244acc6ab6e9f2dcd2bf0e7348f2a524ddc34823994d73c3846356425a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Dose-Response Relationship, Drug</topic><topic>Frontotemporal Dementia - drug therapy</topic><topic>Frontotemporal Dementia - metabolism</topic><topic>HEK293 Cells</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Intercellular Signaling Peptides and Proteins - biosynthesis</topic><topic>Neurobiology</topic><topic>Progranulins</topic><topic>Transcription, Genetic - drug effects</topic><topic>Up-Regulation - drug effects</topic><topic>Vorinostat</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cenik, Basar</creatorcontrib><creatorcontrib>Sephton, Chantelle F</creatorcontrib><creatorcontrib>Dewey, Colleen M</creatorcontrib><creatorcontrib>Xian, Xunde</creatorcontrib><creatorcontrib>Wei, Shuguang</creatorcontrib><creatorcontrib>Yu, Kimberley</creatorcontrib><creatorcontrib>Niu, Wenze</creatorcontrib><creatorcontrib>Coppola, Giovanni</creatorcontrib><creatorcontrib>Coughlin, Sarah E</creatorcontrib><creatorcontrib>Lee, Suzee E</creatorcontrib><creatorcontrib>Dries, Daniel R</creatorcontrib><creatorcontrib>Almeida, Sandra</creatorcontrib><creatorcontrib>Geschwind, Daniel H</creatorcontrib><creatorcontrib>Gao, Fen-Biao</creatorcontrib><creatorcontrib>Miller, Bruce L</creatorcontrib><creatorcontrib>Farese, Jr, Robert V</creatorcontrib><creatorcontrib>Posner, Bruce A</creatorcontrib><creatorcontrib>Yu, Gang</creatorcontrib><creatorcontrib>Herz, Joachim</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cenik, Basar</au><au>Sephton, Chantelle F</au><au>Dewey, Colleen M</au><au>Xian, Xunde</au><au>Wei, Shuguang</au><au>Yu, Kimberley</au><au>Niu, Wenze</au><au>Coppola, Giovanni</au><au>Coughlin, Sarah E</au><au>Lee, Suzee E</au><au>Dries, Daniel R</au><au>Almeida, Sandra</au><au>Geschwind, Daniel H</au><au>Gao, Fen-Biao</au><au>Miller, Bruce L</au><au>Farese, Jr, Robert V</au><au>Posner, Bruce A</au><au>Yu, Gang</au><au>Herz, Joachim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-05-06</date><risdate>2011</risdate><volume>286</volume><issue>18</issue><spage>16101</spage><epage>16108</epage><pages>16101-16108</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. 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| subjects | Dose-Response Relationship, Drug Frontotemporal Dementia - drug therapy Frontotemporal Dementia - metabolism HEK293 Cells Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - pharmacology Intercellular Signaling Peptides and Proteins - biosynthesis Neurobiology Progranulins Transcription, Genetic - drug effects Up-Regulation - drug effects Vorinostat |
| title | Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia |
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