title: Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia.
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.
authors.affiliation: Departments of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1901 East Road, Houston, TX 77054, USA. dsampath@mdanderson.org
authors.forename: Deepa
authors.initials: D
authors.lastname: Sampath
authors.forename: Chaomei
authors.initials: C
authors.lastname: Liu
authors.forename: Karthik
authors.initials: K
authors.lastname: Vasan
authors.forename: Melanie
authors.initials: M
authors.lastname: Sulda
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Puduvalli
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
mesh_terms: D000328:Adult; D001549:Benzamides / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D000077767:Panobinostat; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D011725:Pyridines; C118739:entinostat; D000077767:Panobinostat; D006655:Histone Deacetylases
references.citation: Blood. 2009 Apr 16;113(16):3744-53
references.pmid: 19096009
references.citation: Blood. 2009 Jul 9;114(2):380-93
references.pmid: 19383971
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Genome Res. 2008 Apr;18(4):521-32
references.pmid: 18347325
references.citation: Blood. 2010 Dec 2;116(23):e118-27
references.pmid: 20733160
references.citation: N Engl J Med. 2005 Oct 27;353(17):1793-801
references.pmid: 16251535
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12210-5
references.pmid: 20566844
references.citation: Leukemia. 2008 Apr;22(4):819-25
references.pmid: 18239621
references.citation: Blood. 2009 Jan 8;113(2):396-402
references.pmid: 18941111
references.citation: Nat Med. 2008 Nov;14(11):1271-7
references.pmid: 18931683
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5166-71
references.pmid: 18362358
references.citation: Cancer Res. 2006 Dec 15;66(24):11590-3
references.pmid: 17178851
references.citation: Cancer Res. 2008 Feb 15;68(4):1012-21
references.pmid: 18281475
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9
references.pmid: 16166262
references.citation: Blood. 2009 Jan 15;113(3):535-7
references.pmid: 19008456
references.citation: Biol Chem. 2008 Apr;389(4):383-93
references.pmid: 18208354
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11755-60
references.pmid: 15284443
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004
references.pmid: 14973191
references.citation: Blood. 2009 Dec 17;114(26):5331-41
references.pmid: 19850741
references.citation: Blood. 2008 Nov 1;112(9):3807-17
references.pmid: 18599795
references.citation: Nat Genet. 1999 Dec;23(4):474-8
references.pmid: 10581039
references.citation: Cell Res. 2011 Mar;21(3):502-17
references.pmid: 21321605
references.citation: J Biol Chem. 2005 Mar 18;280(11):10491-500
references.pmid: 15637055
references.citation: Mol Cancer Ther. 2010 May;9(5):1349-60
references.pmid: 20406947
references.citation: Mol Med. 2008 Jan-Feb;14(1-2):20-7
references.pmid: 17973028
references.citation: Leukemia. 2009 Dec;23(12):2281-9
references.pmid: 19710697
references.citation: J Clin Invest. 2007 Jan;117(1):112-21
references.pmid: 17200714
references.citation: JAMA. 2011 Jan 5;305(1):59-67
references.pmid: 21205967
references.citation: Future Oncol. 2007 Oct;3(5):521-37
references.pmid: 17927518
references.citation: Cancer Cell. 2010 Apr 13;17(4):333-47
references.pmid: 20385359
references.citation: Exp Cell Res. 2009 Oct 15;315(17):2941-52
references.pmid: 19591824
references.citation: Blood. 2007 Jun 15;109(12):5079-86
references.pmid: 17351108
references.citation: Leukemia. 2008 Feb;22(2):323-9
references.pmid: 17972950
references.citation: Leukemia. 2009 Jun;23(6):1159-63
references.pmid: 19158830
references.citation: Cancer Cell. 2010 Jan 19;17(1):28-40
references.pmid: 20060366
references.citation: Blood. 2009 May 7;113(19):4637-45
references.pmid: 19234140
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references.pmid: 12434020
references.citation: Oncol Rep. 2012 Jan;27(1):10-6
references.pmid: 21971930
references.citation: J Biol Chem. 2008 Apr 11;283(15):9836-43
references.pmid: 18281287
references.citation: Blood. 2009 Jun 18;113(25):6411-8
references.pmid: 19211935
references.citation: Cancer Res. 2006 Jul 1;66(13):6785-92
references.pmid: 16818655
references.citation: Leuk Lymphoma. 2009 Mar;50(3):502-5
references.pmid: 19347735
references.citation: Blood. 2005 Feb 1;105(3):959-67
references.pmid: 15466934
references.citation: Blood. 2007 Jun 1;109(11):4944-51
references.pmid: 17327404
references.citation: Blood. 2011 May 12;117(19):e190-7
references.pmid: 21415268
references.citation: Nat Rev Genet. 2009 Oct;10(10):704-14
references.pmid: 19763153
references.citation: Blood. 2010 Apr 1;115(13):2630-9
references.pmid: 20086245
references.citation: Br J Haematol. 2009 Nov;147(4):507-14
references.pmid: 19747365
references.citation: Science. 2008 Dec 12;322(5908):1695-9
references.pmid: 19008416