title: Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity.
abstract: c-MYC (hereafter MYC) overexpression has been recognized in aggressive B-cell lymphomas and linked to adverse prognosis. MYC activation results in widespread repression of micro-RNA (miRNA) expression and associated with lymphoma aggressive progression. Our recent study identified a MYC-miRNA-EZH2 feed-forward loop linking overexpression of MYC, EZH2 and miRNA repression. Here, using a novel small-molecule BET bromodomain inhibitor, JQ1, and the EZH2 inhibitor, DZNep, we demonstrated that combined treatment of JQ1 and DZNep cooperatively disrupted MYC activation, resulting in a greater restoration of miR-26a expression and synergistically suppressed lymphoma growth and clonogenicity in aggressive lymphoma cells. Furthermore, CHIP assay demonstrated that MYC recruited EZH2 to miR-26a promoter and cooperatively repressed miR-26a expression in aggressive lymphoma cell lines, as well as primary lymphoma cells. Loss- or gain-of-function approaches revealed that miR-26a functioned as a tumor suppressor miRNA and mediated the combinatorial effects of JQ1 and DZNep. These findings represent a novel promising approach for silencing MYC-miRNA-EZH2 amplification loop for combinatorial therapy of aggressive B-cell lymphomas.
authors.affiliation: Department of Malignant Hematology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: T
authors.initials: T
authors.lastname: Lwin
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
authors.forename: S
authors.initials: S
authors.lastname: Chen-Kiang
authors.forename: W S
authors.initials: WS
authors.lastname: Dalton
authors.forename: E
authors.initials: E
authors.lastname: Sotomayor
authors.forename: J
authors.initials: J
authors.lastname: Tao
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D000071221:Enhancer of Zeste Homolog 2 Protein; D016259:Genes, myc; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D017931:DNA Primers; D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
references.citation: Adv Anat Pathol. 2011 May;18(3):219-28
references.pmid: 21490439
references.citation: Leukemia. 2011 Jan;25(1):145-52
references.pmid: 20966935
references.citation: Cancer Cell. 2012 Oct 16;22(4):506-523
references.pmid: 23079660
references.citation: Nature. 2011 Jul 27;476(7360):298-303
references.pmid: 21796119
references.citation: Cancer Res. 2011 Jan 1;71(1):225-33
references.pmid: 21199804
references.citation: Nat Chem Biol. 2012 Nov;8(11):890-6
references.pmid: 23023262
references.citation: EMBO J. 1994 Aug 1;13(15):3487-95
references.pmid: 8062825
references.citation: Leukemia. 2010 Jul;24(7):1335-42
references.pmid: 20485376
references.citation: Nature. 2010 Dec 23;468(7327):1067-73
references.pmid: 20871596
references.citation: Cell. 2012 Mar 30;149(1):22-35
references.pmid: 22464321
references.citation: Curr Biol. 1999 Nov 4;9(21):1255-8
references.pmid: 10556095
references.citation: Blood. 2010 Dec 9;116(24):5247-55
references.pmid: 20736451
references.citation: PLoS One. 2011;6(12):e28585
references.pmid: 22194861
references.citation: Cell. 2011 Sep 16;146(6):904-17
references.pmid: 21889194
references.citation: Blood. 2011 Jun 9;117(23):6227-36
references.pmid: 21460242
references.citation: Nature. 2012 Dec 6;492(7427):108-12
references.pmid: 23051747
references.citation: Int J Cancer. 2000 Sep 15;87(6):787-93
references.pmid: 10956386
references.citation: Blood. 2010 Dec 9;116(24):5228-36
references.pmid: 20841506
references.citation: Nature. 2005 Jun 9;435(7043):828-33
references.pmid: 15944707
references.citation: Cell Death Dis. 2010 Oct 21;1:e85
references.pmid: 21368858
references.citation: Nature. 1985 Dec 12-18;318(6046):533-8
references.pmid: 3906410
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20980-5
references.pmid: 21078963
references.citation: Oncogene. 2012 Jun 14;31(24):3002-3008
references.pmid: 22002311
references.citation: Mol Cancer Ther. 2009 Jun;8(6):1579-88
references.pmid: 19509260
references.citation: Nat Genet. 2011 Jul 31;43(9):830-7
references.pmid: 21804550
references.citation: Br J Haematol. 2001 Mar;112(4):950-8
references.pmid: 11298590
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74
references.pmid: 21949397
references.citation: Blood. 2008 Nov 15;112(10):4202-12
references.pmid: 18713946
references.citation: Leukemia. 2011 Apr;25(4):726-9
references.pmid: 21233829
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5
references.pmid: 23236167
references.citation: Leukemia. 2013 Mar;27(3):523-33
references.pmid: 23257781
references.citation: Am J Pathol. 2010 Aug;177(2):930-42
references.pmid: 20558579
references.citation: Cancer Discov. 2012 May;2(5):405-13
references.pmid: 22588878
references.citation: Nat Genet. 2008 Jan;40(1):43-50
references.pmid: 18066065
references.citation: Nat Genet. 2010 Feb;42(2):181-5
references.pmid: 20081860
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84
references.pmid: 22343534