title: Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer.
abstract: Tumor metastasis is the leading cause of death among breast cancer patients. PELP1 (proline, glutamic acid and leucine rich protein 1) is a nuclear receptor coregulator that is upregulated during breast cancer progression to metastasis and is an independent prognostic predictor of shorter survival of breast cancer patients. Here, we show that PELP1 modulates expression of metastasis-influencing microRNAs (miRs) to promote cancer metastasis. Whole genome miR array analysis using PELP1-overexpressing and PELP1-underexpressing model cells revealed that miR-200 and miR-141 levels inversely correlated with PELP1 expression. Consistent with this, PELP1 knockdown resulted in lower expression of miR-200a target genes ZEB1 and ZEB2. PELP1 knockdown significantly reduced tumor growth and metastasis compared with parental cells in an orthotopic xenograft tumor model. Furthermore, re-introduction of miR-200a and miR-141 mimetics into PELP1-overexpressing cells reversed PELP1 target gene expression, decreased PELP1-driven migration/invasion in vitro and significantly reduced in vivo metastatic potential in a preclinical model of experimental metastasis. Our results demonstrated that PELP1 binds to miR-200a and miR-141 promoters and regulates their expression by recruiting chromatin modifier histone deacetylase 2 (HDAC2) as revealed by chromatin immunoprecipitation, small interfering RNA and HDAC inhibitor assays. Taken together, our results suggest that PELP1 regulates tumor metastasis by controlling the expression and functions of the tumor metastasis suppressors miR-200a and miR-141.
authors: Department of Obstetrics and Gynecology, UT Health Science Center, San Antonio, TX, USA.
authors: S S
authors: SS
authors: Roy
authors: Department of Obstetrics and Gynecology, UT Health Science Center, San Antonio, TX, USA.
authors: V K
authors: VK
authors: Gonugunta
authors: Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA.
authors: A
authors: A
authors: Bandyopadhyay
authors: 1] Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA [2] Cancer Therapy and Research Center, UT Health Science Center, San Antonio, TX, USA.
authors: M K
authors: MK
authors: Rao
authors: Center for Cancer Biology, SA Pathology, Department of Medicine, School of Molecular and Biomedical science, University of Adelaide, Adelaide, South Australia, Australia.
authors: G J
authors: GJ
authors: Goodall
authors: 1] Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA [2] Cancer Therapy and Research Center, UT Health Science Center, San Antonio, TX, USA.
authors: L-Z
authors: LZ
authors: Sun
authors: 1] Department of Obstetrics and Gynecology, UT Health Science Center, San Antonio, TX, USA [2] Cancer Therapy and Research Center, UT Health Science Center, San Antonio, TX, USA.
authors: R R
authors: RR
authors: Tekmal
authors: 1] Department of Obstetrics and Gynecology, UT Health Science Center, San Antonio, TX, USA [2] Cancer Therapy and Research Center, UT Health Science Center, San Antonio, TX, USA.
authors: R K
authors: RK
authors: Vadlamudi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C438485:PELP1 protein, human; D014157:Transcription Factors; D056464:Histone Deacetylase 2
references: J Biol Chem. 2004 Dec 3;279(49):50930-41
references: 15456770
references: Cancer Res. 2009 May 1;69(9):3819-27
references: 19383905
references: Minerva Ginecol. 2012 Feb;64(1):75-88
references: 22334233
references: Cancer Res. 2008 May 15;68(10):3645-54
references: 18483246
references: Genes Dev. 2006 Jun 1;20(11):1405-28
references: 16751179
references: Cancer Res. 2010 Sep 15;70(18):7166-75
references: 20807815
references: Breast Cancer Res. 2010;12(3):R29
references: 20497549
references: FASEB J. 1993 Dec;7(15):1434-41
references: 8262328
references: PLoS One. 2010 Apr 28;5(4):e10365
references: 20442777
references: Mol Cell Biol. 2008 Oct;28(19):5937-50
references: 18644862
references: Nat Cell Biol. 2001 Jan;3(1):30-7
references: 11146623
references: Cancer Res. 2005 Aug 15;65(16):7065-70
references: 16103053
references: Nucl Recept Signal. 2007 May 17;5:e004
references: 17525794
references: Breast Cancer Res. 2012 Jul 19;14(4):R108
references: 22812534
references: Cancer Res. 2009 Oct 1;69(19):7495-8
references: 19773429
references: J Clin Invest. 2009 Jun;119(6):1438-49
references: 19487820
references: Cancer Metastasis Rev. 2010 Dec;29(4):785-99
references: 20938719
references: Mol Endocrinol. 2007 May;21(5):1009-13
references: 17284664
references: Cancer Res. 2009 Nov 1;69(21):8217-22
references: 19843848
references: Int J Breast Cancer. 2012;2012:654698
references: 22295247
references: Clin Cancer Res. 2011 Apr 15;17(8):2250-9
references: 21421858
references: Cancer Res. 2007 Jun 1;67(11):5505-12
references: 17545633
references: J Clin Pathol. 2009 May;62(5):422-8
references: 19398594
references: Cancer Res. 2008 Oct 1;68(19):7846-54
references: 18829540
references: Nat Cell Biol. 2011 Mar;13(3):317-23
references: 21336307
references: Breast Cancer Res Treat. 2010 Apr;120(3):603-12
references: 19495959
references: Mol Endocrinol. 2007 Mar;21(3):613-24
references: 17192406
references: EMBO Rep. 2008 Jun;9(6):582-9
references: 18483486
references: IUBMB Life. 2010 Mar;62(3):162-9
references: 20014005
references: Nat Rev Drug Discov. 2012 Jun 01;11(6):479-97
references: 22653217
references: Mol Cancer Res. 2012 Jan;10(1):25-33
references: 22086908
references: Eur J Cancer. 2000 Aug;36(13 Spec No):1607-20
references: 10959047
references: J Clin Invest. 2011 Apr;121(4):1373-85
references: 21403400
references: Oncogene. 2012 May 17;31(20):2499-511
references: 21963843
references: Int J Cancer. 2011 Mar 15;128(6):1327-34
references: 20473948
references: EMBO Rep. 2010 Jun;11(6):438-44
references: 20448663
references: Cancer Res. 2010 May 15;70(10):4092-101
references: 20460518
references: Science. 2006 Sep 22;313(5794):1749-50
references: 16990541
references: Nat Cell Biol. 2008 May;10(5):593-601
references: 18376396
references: Cancer Chemother Pharmacol. 2005 Nov;56 Suppl 1:10-20
references: 16273359
references: Breast Cancer Res. 2005;7(4):R444-54
references: 15987449
references: Nat Med. 2006 Aug;12(8):895-904
references: 16892035