Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.
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.
Yang
Muh-Hwa
MH
Institute of Clinical Medicine, National Yang-Ming University, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan. mhyang2@vghtpe.gov.tw
Hsu
Dennis Shin-Shian
DS
Wang
Hsei-Wei
HW
Wang
Hsiao-Jung
HJ
Lan
Hsin-Yi
HY
Yang
Wen-Hao
WH
Huang
Chi-Hung
CH
Kao
Shou-Yen
SY
Tzeng
Cheng-Hwai
CH
Tai
Shyh-Kuan
SK
Chang
Shyue-Yih
SY
Lee
Oscar Kuang-Sheng
OK
Wu
Kou-Juey
KJ
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*
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
Science. 2001 Aug 31;293(5535):1629-33
11486054
Br J Cancer. 2007 Jan 15;96(1):126-33
17179983
Cell. 2002 Oct 18;111(2):197-208
12408864
Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):913-8
19215825
Biochem Biophys Res Commun. 2009 Jul 31;385(3):307-13
19450560
Immunity. 2004 Dec;21(6):843-51
15589172
Cell. 2009 Nov 25;139(5):871-90
19945376
Nature. 2006 Aug 17;442(7104):823-6
16799564
Nature. 2003 Oct 30;425(6961):962-7
14574365
Mol Cell Biol. 2008 May;28(10):3198-207
18347060
Cell. 2004 Aug 20;118(4):409-18
15315754
Cell. 2008 May 16;133(4):704-15
18485877
Cell. 2007 May 4;129(3):465-72
17482542
Head Neck. 2005 Jul;27(7):622-38
15952198
Clin Cancer Res. 2006 Jan 15;12(2):507-15
16428493
Am J Pathol. 2010 Feb;176(2):699-709
20035051
Mol Cell Biol. 2004 Jan;24(1):306-19
14673164
Mol Cell Biol. 2008 Aug;28(15):4772-81
18519590
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92
9653127
Genes Dev. 2004 Jan 1;18(1):99-115
14701881
Mol Cell Biol. 2004 Mar;24(6):2444-54
14993282
Genes Dev. 2005 Jun 15;19(12):1438-43
15964995
Head Neck. 2008 Nov;30(11):1475-82
18704970
Oncogene. 2007 Mar 1;26(10):1459-67
16936774
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
17210912
Cell Stem Cell. 2007 Nov;1(5):555-67
18371393
Nat Genet. 2008 Jul;40(7):915-20
18536716
Cell. 2002 Oct 18;111(2):185-96
12408863
Stem Cells. 2008 May;26(5):1186-201
18308945
Nature. 2004 Mar 18;428(6980):337-41
15029199
Nat Cell Biol. 2009 Dec;11(12):1487-95
19935649
Dev Cell. 2005 Nov;9(5):617-28
16256737
J Clin Oncol. 2008 Jul 1;26(19):3128-37
18474878
Neoplasia. 2009 Dec;11(12):1371-82
20019845
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13427-32
18765800
Br J Cancer. 2005 Apr 25;92(8):1341-8
15846296
Cancer Res. 2008 Oct 1;68(19):7742-9
18829528
Genes Dev. 2003 Aug 1;17(15):1823-8
12897052
PLoS One. 2008 Aug 06;3(8):e2888
18682804
Genes Dev. 2007 Mar 1;21(5):525-30
17344414
Nat Genet. 2007 Feb;39(2):157-8
17200673
Oncogene. 2008 Dec 11;27(58):7274-84
18806826
Cell. 2004 Jun 25;117(7):927-39
15210113
Head Neck. 2007 Jun;29(6):591-604
17252597
Nat Genet. 2004 Jul;36(7):687-93
15220918
Genome Biol. 2008;9(5):R83
18492237
Cell Cycle. 2008 Jul 15;7(14):2090-6
18635960
Genes Dev. 1999 Oct 15;13(20):2678-90
10541554
Nat Cell Biol. 2008 Mar;10(3):295-305
18297062
J Natl Cancer Inst. 2000 Apr 5;92(7):569-73
10749913
Nature. 1999 Jan 14;397(6715):164-8
9923679