Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by whi...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Blood 2012-02, Vol.119 (5), p.1162-1172
Hauptverfasser: Sampath, Deepa, Liu, Chaomei, Vasan, Karthik, Sulda, Melanie, Puduvalli, Vinay K., Wierda, William G., Keating, Michael J.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1172
container_issue 5
container_start_page 1162
container_title Blood
container_volume 119
creator Sampath, Deepa
Liu, Chaomei
Vasan, Karthik
Sulda, Melanie
Puduvalli, Vinay K.
Wierda, William G.
Keating, Michael J.
description Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor–based therapy.
doi_str_mv 10.1182/blood-2011-05-351510
format Article
fullrecord <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3277352</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006497120461427</els_id><sourcerecordid>22096249</sourcerecordid><originalsourceid>FETCH-LOGICAL-c558t-ee400e5018800f2fe78d152818fe71ae1cebeec272b95b6018459cbe2cd4c6b73</originalsourceid><addsrcrecordid>eNp9kc1KAzEUhYMotlbfQCQbd0ZvMpP52QgiagVBEF2HTOZOmzozKcko9O1NrVrduMqBnHuS811Cjjmcc16Ii6p1rmYCOGcgWSK55LBDxlyKggEI2CVjAMhYWuZ8RA5CWADwNBFyn4yEgDITaTkmi6kNg-uR1qgNDqtWBwy0w9rqAekwRxpsi72x_Yy6hnb2iXGpzzYiO6O6rz-1KCtqe2rm3vXW0HbVLefOrIa1xrdX7Kw-JHuNbgMefZ0T8nJ783w9ZQ-Pd_fXVw_MSFkMDDEFQAm8KAAa0WBe1OtSvIiSa-QGK0QjclGVssqiL5WlqVCYOjVZlScTcrnJXb5VsYjBfvC6VUtvO-1Xymmr_t70dq5m7l0lIs8TKWJAugkw3oXgsfmZ5aDW7NUne7Vmr0CqDfs4dvL73Z-hb9jRcPpl0MHotvE6cg1bn5SZLHOxLYCR0rtFr4KxcQdxKR7NoGpn___JB9gYo54</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia</title><source>MEDLINE</source><source>Free E-Journal (出版社公開部分のみ)</source><source>Alma/SFX Local Collection</source><creator>Sampath, Deepa ; Liu, Chaomei ; Vasan, Karthik ; Sulda, Melanie ; Puduvalli, Vinay K. ; Wierda, William G. ; Keating, Michael J.</creator><creatorcontrib>Sampath, Deepa ; Liu, Chaomei ; Vasan, Karthik ; Sulda, Melanie ; Puduvalli, Vinay K. ; Wierda, William G. ; Keating, Michael J.</creatorcontrib><description>Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor–based therapy.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-05-351510</identifier><identifier>PMID: 22096249</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Adult ; Benzamides - pharmacology ; Biological and medical sciences ; Female ; Gene Expression Regulation, Leukemic - drug effects ; Gene Silencing - drug effects ; Gene Silencing - physiology ; Hematologic and hematopoietic diseases ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - genetics ; Histone Deacetylases - physiology ; Humans ; Hydroxamic Acids - pharmacology ; Indoles ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphoid Neoplasia ; Male ; Medical sciences ; MicroRNAs - genetics ; Panobinostat ; Primary Cell Culture ; Pyridines - pharmacology ; Tumor Cells, Cultured</subject><ispartof>Blood, 2012-02, Vol.119 (5), p.1162-1172</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><rights>2012 by The American Society of Hematology 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c558t-ee400e5018800f2fe78d152818fe71ae1cebeec272b95b6018459cbe2cd4c6b73</citedby><cites>FETCH-LOGICAL-c558t-ee400e5018800f2fe78d152818fe71ae1cebeec272b95b6018459cbe2cd4c6b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=25565972$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22096249$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sampath, Deepa</creatorcontrib><creatorcontrib>Liu, Chaomei</creatorcontrib><creatorcontrib>Vasan, Karthik</creatorcontrib><creatorcontrib>Sulda, Melanie</creatorcontrib><creatorcontrib>Puduvalli, Vinay K.</creatorcontrib><creatorcontrib>Wierda, William G.</creatorcontrib><creatorcontrib>Keating, Michael J.</creatorcontrib><title>Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia</title><title>Blood</title><addtitle>Blood</addtitle><description>Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor–based therapy.</description><subject>Adult</subject><subject>Benzamides - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Female</subject><subject>Gene Expression Regulation, Leukemic - drug effects</subject><subject>Gene Silencing - drug effects</subject><subject>Gene Silencing - physiology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - physiology</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Indoles</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphoid Neoplasia</subject><subject>Male</subject><subject>Medical sciences</subject><subject>MicroRNAs - genetics</subject><subject>Panobinostat</subject><subject>Primary Cell Culture</subject><subject>Pyridines - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1KAzEUhYMotlbfQCQbd0ZvMpP52QgiagVBEF2HTOZOmzozKcko9O1NrVrduMqBnHuS811Cjjmcc16Ii6p1rmYCOGcgWSK55LBDxlyKggEI2CVjAMhYWuZ8RA5CWADwNBFyn4yEgDITaTkmi6kNg-uR1qgNDqtWBwy0w9rqAekwRxpsi72x_Yy6hnb2iXGpzzYiO6O6rz-1KCtqe2rm3vXW0HbVLefOrIa1xrdX7Kw-JHuNbgMefZ0T8nJ783w9ZQ-Pd_fXVw_MSFkMDDEFQAm8KAAa0WBe1OtSvIiSa-QGK0QjclGVssqiL5WlqVCYOjVZlScTcrnJXb5VsYjBfvC6VUtvO-1Xymmr_t70dq5m7l0lIs8TKWJAugkw3oXgsfmZ5aDW7NUne7Vmr0CqDfs4dvL73Z-hb9jRcPpl0MHotvE6cg1bn5SZLHOxLYCR0rtFr4KxcQdxKR7NoGpn___JB9gYo54</recordid><startdate>20120202</startdate><enddate>20120202</enddate><creator>Sampath, Deepa</creator><creator>Liu, Chaomei</creator><creator>Vasan, Karthik</creator><creator>Sulda, Melanie</creator><creator>Puduvalli, Vinay K.</creator><creator>Wierda, William G.</creator><creator>Keating, Michael J.</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>20120202</creationdate><title>Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia</title><author>Sampath, Deepa ; Liu, Chaomei ; Vasan, Karthik ; Sulda, Melanie ; Puduvalli, Vinay K. ; Wierda, William G. ; Keating, Michael J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c558t-ee400e5018800f2fe78d152818fe71ae1cebeec272b95b6018459cbe2cd4c6b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Benzamides - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Female</topic><topic>Gene Expression Regulation, Leukemic - drug effects</topic><topic>Gene Silencing - drug effects</topic><topic>Gene Silencing - physiology</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - genetics</topic><topic>Histone Deacetylases - physiology</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Indoles</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Lymphoid Neoplasia</topic><topic>Male</topic><topic>Medical sciences</topic><topic>MicroRNAs - genetics</topic><topic>Panobinostat</topic><topic>Primary Cell Culture</topic><topic>Pyridines - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sampath, Deepa</creatorcontrib><creatorcontrib>Liu, Chaomei</creatorcontrib><creatorcontrib>Vasan, Karthik</creatorcontrib><creatorcontrib>Sulda, Melanie</creatorcontrib><creatorcontrib>Puduvalli, Vinay K.</creatorcontrib><creatorcontrib>Wierda, William G.</creatorcontrib><creatorcontrib>Keating, Michael J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</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>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sampath, Deepa</au><au>Liu, Chaomei</au><au>Vasan, Karthik</au><au>Sulda, Melanie</au><au>Puduvalli, Vinay K.</au><au>Wierda, William G.</au><au>Keating, Michael J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-02-02</date><risdate>2012</risdate><volume>119</volume><issue>5</issue><spage>1162</spage><epage>1172</epage><pages>1162-1172</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of miR-15a and miR-16 and a selective silencing of the related miR-29b in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. In the present study, we show that the histone deacetylases (HDACs) are overexpressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16, and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification H3K4me2 and restored the expression of miR-15a, miR-16, and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 and HDAC inhibition–induced expression of miR-15a, miR-16, or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction, and induction of cell death. Therefore, our results show that HDACs aberrantly silence the expression of the critical tumor suppressors miR-15a, miR-16, and miR-29b in CLL. Deacetylase inhibition may be a therapeutic strategy that restores the expression of these miRs to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients who exhibit such epigenetic silencing may benefit from HDAC inhibitor–based therapy.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22096249</pmid><doi>10.1182/blood-2011-05-351510</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0006-4971
ispartof Blood, 2012-02, Vol.119 (5), p.1162-1172
issn 0006-4971
1528-0020
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3277352
source MEDLINE; Free E-Journal (出版社公開部分のみ); Alma/SFX Local Collection
subjects Adult
Benzamides - pharmacology
Biological and medical sciences
Female
Gene Expression Regulation, Leukemic - drug effects
Gene Silencing - drug effects
Gene Silencing - physiology
Hematologic and hematopoietic diseases
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - genetics
Histone Deacetylases - physiology
Humans
Hydroxamic Acids - pharmacology
Indoles
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Lymphoid Neoplasia
Male
Medical sciences
MicroRNAs - genetics
Panobinostat
Primary Cell Culture
Pyridines - pharmacology
Tumor Cells, Cultured
title Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T09%3A36%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Histone%20deacetylases%20mediate%20the%20silencing%20of%20miR-15a,%20miR-16,%20and%20miR-29b%20in%20chronic%20lymphocytic%20leukemia&rft.jtitle=Blood&rft.au=Sampath,%20Deepa&rft.date=2012-02-02&rft.volume=119&rft.issue=5&rft.spage=1162&rft.epage=1172&rft.pages=1162-1172&rft.issn=0006-4971&rft.eissn=1528-0020&rft_id=info:doi/10.1182/blood-2011-05-351510&rft_dat=%3Cpubmed_cross%3E22096249%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/22096249&rft_els_id=S0006497120461427&rfr_iscdi=true