title: Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.
abstract: The epithelial-mesenchymal transition (EMT), one of the main mechanisms underlying development of cancer metastasis, induces stem-like properties in epithelial cells. Bmi1 is a polycomb-group protein that maintains self-renewal, and is frequently overexpressed in human cancers. Here, we show the direct regulation of BMI1 by the EMT regulator, Twist1. Furthermore, Twist1 and Bmi1 were mutually essential to promote EMT and tumour-initiating capability. Twist1 and Bmi1 act cooperatively to repress expression of both E-cadherin and p16INK4a. In patients with head and neck cancers, increased levels of both Twist1 and Bmi1 correlated with downregulation of E-cadherin and p16INK4a, and was associated with the worst prognosis. These results suggest that Twist1-induced EMT and tumour-initiating capability in cancer cells occurs through chromatin remodelling, which leads to unfavourable clinical outcomes.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan. mhyang2@vghtpe.gov.tw
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.forename: Dennis Shin-Shian
authors.initials: DS
authors.lastname: Hsu
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Hsiao-Jung
authors.initials: HJ
authors.lastname: Wang
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lan
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Yang
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Shyue-Yih
authors.initials: SY
authors.lastname: Chang
authors.forename: Oscar Kuang-Sheng
authors.initials: OK
authors.lastname: Lee
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D019942:Genes, p16; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C069077:BMI1 protein, human; D015820:Cadherins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D063150:Polycomb Repressive Complex 1
references.citation: Science. 2001 Aug 31;293(5535):1629-33
references.pmid: 11486054
references.citation: Br J Cancer. 2007 Jan 15;96(1):126-33
references.pmid: 17179983
references.citation: Cell. 2002 Oct 18;111(2):197-208
references.pmid: 12408864
references.citation: Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):913-8
references.pmid: 19215825
references.citation: Biochem Biophys Res Commun. 2009 Jul 31;385(3):307-13
references.pmid: 19450560
references.citation: Immunity. 2004 Dec;21(6):843-51
references.pmid: 15589172
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Nature. 2006 Aug 17;442(7104):823-6
references.pmid: 16799564
references.citation: Nature. 2003 Oct 30;425(6961):962-7
references.pmid: 14574365
references.citation: Mol Cell Biol. 2008 May;28(10):3198-207
references.pmid: 18347060
references.citation: Cell. 2004 Aug 20;118(4):409-18
references.pmid: 15315754
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Cell. 2007 May 4;129(3):465-72
references.pmid: 17482542
references.citation: Head Neck. 2005 Jul;27(7):622-38
references.pmid: 15952198
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):507-15
references.pmid: 16428493
references.citation: Am J Pathol. 2010 Feb;176(2):699-709
references.pmid: 20035051
references.citation: Mol Cell Biol. 2004 Jan;24(1):306-19
references.pmid: 14673164
references.citation: Mol Cell Biol. 2008 Aug;28(15):4772-81
references.pmid: 18519590
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92
references.pmid: 9653127
references.citation: Genes Dev. 2004 Jan 1;18(1):99-115
references.pmid: 14701881
references.citation: Mol Cell Biol. 2004 Mar;24(6):2444-54
references.pmid: 14993282
references.citation: Genes Dev. 2005 Jun 15;19(12):1438-43
references.pmid: 15964995
references.citation: Head Neck. 2008 Nov;30(11):1475-82
references.pmid: 18704970
references.citation: Oncogene. 2007 Mar 1;26(10):1459-67
references.pmid: 16936774
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
references.pmid: 17210912
references.citation: Cell Stem Cell. 2007 Nov;1(5):555-67
references.pmid: 18371393
references.citation: Nat Genet. 2008 Jul;40(7):915-20
references.pmid: 18536716
references.citation: Cell. 2002 Oct 18;111(2):185-96
references.pmid: 12408863
references.citation: Stem Cells. 2008 May;26(5):1186-201
references.pmid: 18308945
references.citation: Nature. 2004 Mar 18;428(6980):337-41
references.pmid: 15029199
references.citation: Nat Cell Biol. 2009 Dec;11(12):1487-95
references.pmid: 19935649
references.citation: Dev Cell. 2005 Nov;9(5):617-28
references.pmid: 16256737
references.citation: J Clin Oncol. 2008 Jul 1;26(19):3128-37
references.pmid: 18474878
references.citation: Neoplasia. 2009 Dec;11(12):1371-82
references.pmid: 20019845
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13427-32
references.pmid: 18765800
references.citation: Br J Cancer. 2005 Apr 25;92(8):1341-8
references.pmid: 15846296
references.citation: Cancer Res. 2008 Oct 1;68(19):7742-9
references.pmid: 18829528
references.citation: Genes Dev. 2003 Aug 1;17(15):1823-8
references.pmid: 12897052
references.citation: PLoS One. 2008 Aug 06;3(8):e2888
references.pmid: 18682804
references.citation: Genes Dev. 2007 Mar 1;21(5):525-30
references.pmid: 17344414
references.citation: Nat Genet. 2007 Feb;39(2):157-8
references.pmid: 17200673
references.citation: Oncogene. 2008 Dec 11;27(58):7274-84
references.pmid: 18806826
references.citation: Cell. 2004 Jun 25;117(7):927-39
references.pmid: 15210113
references.citation: Head Neck. 2007 Jun;29(6):591-604
references.pmid: 17252597
references.citation: Nat Genet. 2004 Jul;36(7):687-93
references.pmid: 15220918
references.citation: Genome Biol. 2008;9(5):R83
references.pmid: 18492237
references.citation: Cell Cycle. 2008 Jul 15;7(14):2090-6
references.pmid: 18635960
references.citation: Genes Dev. 1999 Oct 15;13(20):2678-90
references.pmid: 10541554
references.citation: Nat Cell Biol. 2008 Mar;10(3):295-305
references.pmid: 18297062
references.citation: J Natl Cancer Inst. 2000 Apr 5;92(7):569-73
references.pmid: 10749913
references.citation: Nature. 1999 Jan 14;397(6715):164-8
references.pmid: 9923679