title: SETD6 controls the expression of estrogen-responsive genes and proliferation of breast carcinoma cells.
abstract: The lysine methyltransferase SETD6 modifies the histone variant H2AZ, a key component of nuclear receptor-dependent transcription. Herein, we report the identification of several factors that associate with SETD6 and are implicated in nuclear hormone receptor signaling. Specifically, SETD6 associates with the estrogen receptor α (ERα), histone deacetylase HDAC1, metastasis protein MTA2, and the transcriptional co-activator TRRAP. Luciferase reporter assays identify SETD6 as a transcriptional repressor, in agreement with its association with HDAC1 and MTA2. However, SETD6 behaves as a co-activator of several estrogen-responsive genes, such as PGR and TFF1. Consistent with these results, silencing of SETD6 in several breast carcinoma cell lines induced cellular proliferation defects accompanied by enhanced expression of the cell cycle inhibitor CDKN1A and induction of apoptosis. Herein, we have identified several chromatin proteins that associate with SETD6 and described SETD6 as an essential factor for nuclear receptor signaling and cellular proliferation.
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Neill
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Stuart Charles
authors.initials: SC
authors.lastname: Williamson
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Dhuha
authors.initials: D
authors.lastname: Alkharaif
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Isabella Christina Mazzaro
authors.initials: IC
authors.lastname: Monteiro
authors.affiliation: Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto, ON Canada.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Goudreault
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto, ON Canada; Department of Molecular Genetics; University of Toronto; Toronto, ON Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Northern Institute for Cancer Research; Newcastle University; Newcastle upon Tyne, UK.
authors.forename: Olivier
authors.initials: O
authors.lastname: Binda
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011496:Protein Methyltransferases / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009687:Nuclear Proteins; D012097:Repressor Proteins; D011496:Protein Methyltransferases; C562071:SETD6 protein, human; C120917:MTA2 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
keywords: SETD6; cellular proliferation; estrogen receptor; lysine methyltransferase
references.citation: J Cell Biochem. 1993 Feb;51(2):135-9
references.pmid: 8440747
references.citation: J Biol Chem. 2011 Dec 9;286(49):41963-41971
references.pmid: 21984853
references.citation: J Biol Chem. 2011 Jul 15;286(28):25065-75
references.pmid: 21561862
references.citation: Mol Cell. 2006 Feb 3;21(3):393-404
references.pmid: 16455494
references.citation: Nat Immunol. 2011 Jan;12(1):29-36
references.pmid: 21131967
references.citation: Nat Rev Cancer. 2013 Jan;13(1):27-36
references.pmid: 23192231
references.citation: Cell. 2005 Jun 17;121(6):873-85
references.pmid: 15960975
references.citation: Biochemistry. 1964 Jan;3:10-5
references.pmid: 14114491
references.citation: Mol Cell Biol. 2008 Apr;28(7):2257-70
references.pmid: 18212047
references.citation: Nat Struct Mol Biol. 2011 Nov 13;18(12):1358-65
references.pmid: 22081016
references.citation: Cell. 1993 Jan 15;72(1):73-84
references.pmid: 8422685
references.citation: Nature. 1988 Jul 7;334(6177):31-6
references.pmid: 3290686
references.citation: Nature. 2009 Jul 9;460(7252):287-91
references.pmid: 19483677
references.citation: Cell. 2009 Sep 4;138(5):1019-31
references.pmid: 19698979
references.citation: PLoS Genet. 2013;9(1):e1003210
references.pmid: 23349634
references.citation: Curr Opin Genet Dev. 2005 Jun;15(3):227-33
references.pmid: 15917196
references.citation: PLoS One. 2013 Oct 02;8(10):e74799
references.pmid: 24098348
references.citation: Cancer Res. 1976 Dec;36(12):4595-601
references.pmid: 1000504
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19176-81
references.pmid: 17142323
references.citation: Nat Genet. 2007 May;39(5):655-60
references.pmid: 17417639
references.citation: Nature. 1986 Mar 13-19;320(6058):134-9
references.pmid: 3754034
references.citation: Cell. 2005 Sep 23;122(6):957-68
references.pmid: 16169070
references.citation: J Biol Chem. 2003 Oct 24;278(43):42560-8
references.pmid: 12920132
references.citation: J Mol Biol. 2001 Apr 6;307(4):977-85
references.pmid: 11286549
references.citation: J Biol Chem. 2004 Apr 9;279(15):15050-8
references.pmid: 14722073
references.citation: Mol Endocrinol. 2006 Sep;20(9):2020-35
references.pmid: 16645043
references.citation: Mol Cell Biol. 2006 Mar;26(5):1917-31
references.pmid: 16479010
references.citation: Oncogene. 2001 Dec 13;20(57):8270-5
references.pmid: 11781841
references.citation: Trends Biochem Sci. 2002 Aug;27(8):396-402
references.pmid: 12151224
references.citation: Epigenetics. 2013 Feb;8(2):177-83
references.pmid: 23324626
references.citation: Mol Cell. 2011 Oct 21;44(2):325-40
references.pmid: 21906983
references.citation: Mol Cell. 2002 Mar;9(3):553-62
references.pmid: 11931763
references.citation: Proc Natl Acad Sci U S A. 1964 May;51:786-94
references.pmid: 14172992
references.citation: Semin Cell Dev Biol. 2010 Apr;21(2):209-20
references.pmid: 19892027
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: EMBO Rep. 2008 Jun;9(6):563-8
references.pmid: 18451880
references.citation: Oncogene. 2008 May 29;27(24):3384-92
references.pmid: 18193082
references.citation: Nature. 2000 Aug 10;406(6796):593-9
references.pmid: 10949293
references.citation: Cell. 1998 Aug 7;94(3):363-74
references.pmid: 9708738
references.citation: Nat Genet. 2001 Oct;29(2):206-11
references.pmid: 11544477
references.citation: Genes Dev. 1999 Aug 1;13(15):1924-35
references.pmid: 10444591
references.citation: J Biol Chem. 1999 Jun 18;274(25):17599-604
references.pmid: 10364196
references.citation: Mol Cell. 2006 Jan 6;21(1):51-64
references.pmid: 16387653
references.citation: Genes Dev. 2013 Jul 15;27(14):1596-609
references.pmid: 23873942
references.citation: J Biol Chem. 1993 Jan 5;268(1):305-14
references.pmid: 8416938
references.citation: Nat Struct Mol Biol. 2012 Dec;19(12):1218-27
references.pmid: 23211769
references.citation: Mol Cell. 2006 Jun 9;22(5):657-68
references.pmid: 16762838
references.citation: Methods. 2012 Aug;57(4):400-8
references.pmid: 22710030
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9545-50
references.pmid: 22623531
references.citation: Oncogene. 2007 Aug 13;26(37):5433-8
references.pmid: 17694084
references.citation: Oncogene. 2007 Aug 13;26(37):5358-72
references.pmid: 17694078
references.citation: Trends Biochem Sci. 2013 May;38(5):243-52
references.pmid: 23490039