title: Elevated NCOR1 disrupts PPARalpha/gamma signaling in prostate cancer and forms a targetable epigenetic lesion.
abstract: The loss of anti-proliferative responsiveness in prostate cancer cell lines toward ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors and peroxisome proliferator activated receptor (PPAR)alpha/gamma may entail underlying epigenetic events, as ligand insensitivity reflects significantly altered messenger RNA expression of corepressors and histone-modifying enzymes. Expression patterns were dependent on phases of the cell cycle and associated with repressed basal gene expression of vitamin D receptor and PPARalpha/gamma target genes, for example CDKN1A [encodes p21((waf1/cip1))]. Elevated nuclear corepressor 1 (NCOR1) and nuclear corepressor 2/silencing mediator of retinoic acid and thyroid hormone receptor protein levels were detected in prostate cancer cell lines compared with non-malignant counterparts. Knockdown of the corepressor NCOR1 significantly elevated basal expression of a cohort of target genes, including CDKN1A. Both chemical [histone deacetylases inhibitor (HDACi)] and NCOR1 knockdown targeting enhanced anti-proliferative sensitivity toward PPARalpha/gamma ligands in prostate cancer cell lines. Pursuing PPARalpha/gamma signaling, microarray approaches were undertaken to identify pathways and genes regulated uniquely by a combination of PPARalpha/gamma activation and HDAC inhibition. Again, HDACi and knockdown approaches demonstrated that elevated NCOR1 expression and activity distorted PPARalpha/gamma gene targets centered on, for example cell cycle control, including CDKN1A and TGFBRAP1. Quantitative real time polymerase chain reaction validation and chromatin immunoprecipitation assays both confirmed that elevated NCOR1 disrupted the ability of PPARalpha/gamma to regulate key target genes (CDKN1A and TGFBRAP1). Interrogation of these relationships in prostate cancer samples using principal component and partial correlation analyses established significant interdependent relationships between NCOR1-PPARalpha/gamma and representative target genes, independently of androgen receptor expression. Therefore, we conclude that elevated NCOR1 distorts the actions of PPARalpha/gamma selectively and generates a potential epigenetic lesion with diagnostic and prognostic significance.
authors.affiliation: Institute of Biomedical Research, Wolfson Drive, University of Birmingham Medical School, Edgbaston, B15 2TT, UK.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Battaglia
authors.forename: Orla
authors.initials: O
authors.lastname: Maguire
authors.forename: James L
authors.initials: JL
authors.lastname: Thorne
authors.forename: Laura B
authors.initials: LB
authors.lastname: Hornung
authors.forename: Craig L
authors.initials: CL
authors.lastname: Doig
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Lara E
authors.initials: LE
authors.lastname: Sucheston
authors.forename: Anna
authors.initials: A
authors.lastname: Bianchi
authors.forename: Farhat L
authors.initials: FL
authors.lastname: Khanim
authors.forename: Lyndon M
authors.initials: LM
authors.lastname: Gommersall
authors.forename: Henry S O
authors.initials: HS
authors.lastname: Coulter
authors.forename: Serena
authors.initials: S
authors.lastname: Rakha
authors.forename: Ian
authors.initials: I
authors.lastname: Giddings
authors.forename: Laura P
authors.initials: LP
authors.lastname: O'Neill
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bunce
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D056971:Nuclear Receptor Co-Repressor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C111893:TGFBRAP1 protein, human
references.citation: Cell. 2009 Jul 23;138(2):245-56
references.pmid: 19632176
references.citation: Stat Methods Med Res. 1992;1(1):69-95
references.pmid: 1341653
references.citation: Biochem J. 2005 Dec 1;392(Pt 2):313-24
references.pmid: 16086669
references.citation: Genome Biol. 2009;10(1):R3
references.pmid: 19133160
references.citation: BMC Bioinformatics. 2006 Feb 01;7:50
references.pmid: 16451725
references.citation: Cell. 2007 May 18;129(4):723-33
references.pmid: 17512406
references.citation: Mol Cell Biol. 2006 Oct;26(20):7561-74
references.pmid: 17015477
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19544-9
references.pmid: 19052228
references.citation: Cancer Res. 2000 Sep 15;60(18):5165-70
references.pmid: 11016644
references.citation: Cancer Res. 2000 Nov 1;60(21):6111-5
references.pmid: 11085535
references.citation: Oncogene. 2001 Apr 5;20(15):1860-72
references.pmid: 11313934
references.citation: J Biol Chem. 2009 Mar 20;284(12):8073-82
references.pmid: 19122196
references.citation: Cell Cycle. 2007 Jul 15;6(14):1748-52
references.pmid: 17630505
references.citation: Nature. 2005 Sep 29;437(7059):759-63
references.pmid: 16127449
references.citation: Nucleic Acids Res. 2004 Sep 01;32(15):4676-86
references.pmid: 15342788
references.citation: Nat Biotechnol. 2003 May;21(5):559-61
references.pmid: 12679785
references.citation: Mol Endocrinol. 2009 Feb;23(2):251-64
references.pmid: 19098224
references.citation: Oncology. 2006;71(1-2):111-23
references.pmid: 17377416
references.citation: Clin Cancer Res. 2002 Apr;8(4):1206-12
references.pmid: 11948134
references.citation: Bioinformatics. 2004 Dec 12;20(18):3565-74
references.pmid: 15284096
references.citation: J Cell Biol. 2001 Jul 23;154(2):369-87
references.pmid: 11470825
references.citation: Genes Dev. 2008 Nov 1;22(21):2941-52
references.pmid: 18981473
references.citation: Cell Growth Differ. 2000 Jan;11(1):49-61
references.pmid: 10672903
references.citation: Blood. 2004 Dec 15;104(13):4226-35
references.pmid: 15319284
references.citation: Neoplasia. 2007 Feb;9(2):166-80
references.pmid: 17356713
references.citation: Endocrinology. 1998 Apr;139(4):1972-80
references.pmid: 9528984
references.citation: EMBO J. 2003 Mar 17;22(6):1336-46
references.pmid: 12628926
references.citation: Genes Dev. 2006 Jun 1;20(11):1405-28
references.pmid: 16751179
references.citation: Nat Rev Genet. 2010 Feb;11(2):109-23
references.pmid: 20084085
references.citation: Biochim Biophys Acta. 2007 Jul;1771(7):864-72
references.pmid: 17500032
references.citation: Carcinogenesis. 2009 Mar;30(3):449-56
references.pmid: 19126649
references.citation: J Immunol. 2002 May 1;168(9):4747-55
references.pmid: 11971025
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2004-13
references.pmid: 16609009
references.citation: Nucleic Acids Res. 2005 Sep 26;33(17):5521-32
references.pmid: 16186133
references.citation: Nucleic Acids Res. 2009 Aug;37(14):4826-38
references.pmid: 19520769
references.citation: Mol Cancer Res. 2007 Sep;5(9):967-80
references.pmid: 17855664
references.citation: Int J Cancer. 2010 Jun 1;126(11):2511-9
references.pmid: 20091860
references.citation: EMBO Rep. 2008 Jun;9(6):563-8
references.pmid: 18451880
references.citation: Oncogene. 2006 Apr 13;25(16):2304-17
references.pmid: 16331265
references.citation: Nat Biotechnol. 2005 Aug;23(8):951-9
references.pmid: 16082366
references.citation: Mol Cell Endocrinol. 2007 Mar 15;267(1-2):138-43
references.pmid: 17668471
references.citation: J Mol Endocrinol. 1997 Aug;19(1):15-27
references.pmid: 9278857
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):20021-6
references.pmid: 19066220
references.citation: J Biol Chem. 2005 Feb 25;280(8):6511-9
references.pmid: 15598662
references.citation: Oncogene. 2004 Sep 2;23(40):6712-25
references.pmid: 15300237
references.citation: Cancer Res. 1999 Nov 1;59(21):5403-7
references.pmid: 10554005
references.citation: Br J Cancer. 1999 Jan;79(1):101-7
references.pmid: 10408700
references.citation: Nature. 2007 Nov 15;450(7168):415-9
references.pmid: 17928865
references.citation: J Med Chem. 2000 Feb 24;43(4):527-50
references.pmid: 10691680
references.citation: Biochim Biophys Acta. 2007 May;1771(5):576-89
references.pmid: 17459764
references.citation: Mol Cell. 2006 Jun 9;22(5):657-68
references.pmid: 16762838
references.citation: Nature. 1998 Feb 19;391(6669):811-4
references.pmid: 9486654
references.citation: Cancer Res. 2006 May 15;66(10):5012-20
references.pmid: 16707422
references.citation: Int J Biochem Cell Biol. 2009 Jan;41(1):164-75
references.pmid: 18804550
references.citation: Science. 2005 Oct 28;310(5748):644-8
references.pmid: 16254181
references.citation: Biochem J. 2008 Mar 1;410(2):245-53
references.pmid: 17988216
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4935-42
references.pmid: 18676768
references.citation: PPAR Res. 2008;2008:314974
references.pmid: 18528521
references.citation: Methods Enzymol. 1996;274:189-97
references.pmid: 8902805
references.citation: Cancer Lett. 2009 Mar 18;275(2):247-55
references.pmid: 19056168
references.citation: J Biol Chem. 2005 Apr 8;280(14):13600-5
references.pmid: 15691842
references.citation: J Biol Chem. 2006 Dec 22;281(51):39607-19
references.pmid: 17062566
references.citation: J Biol Chem. 2003 Feb 14;278(7):5052-61
references.pmid: 12441355