title: ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.
abstract: Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Peijing
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yongkun
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Bisrat G
authors.initials: BG
authors.lastname: Debeb
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Dahu
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.affiliation: 1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan [3] Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: 1] Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1] Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D055550:Protein Stability; D011836:Radiation Tolerance; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
references.citation: Nat Rev Mol Cell Biol. 2006 Oct;7(10):739-50
references.pmid: 16926856
references.citation: Curr Opin Cell Biol. 2001 Dec;13(6):738-47
references.pmid: 11698191
references.citation: Int J Radiat Oncol Biol Phys. 1991 Nov;21(6):1457-69
references.pmid: 1938554
references.citation: Cancer Res. 2009 Mar 15;69(6):2630-7
references.pmid: 19276361
references.citation: Nat Cell Biol. 2005 Feb;7(2):195-201
references.pmid: 15665856
references.citation: J Cell Biol. 2009 Jan 12;184(1):13-9
references.pmid: 19124652
references.citation: Nature. 2004 Apr 1;428(6982):1 p  following 486
references.pmid: 15058298
references.citation: Nature. 2006 Dec 7;444(7120):756-60
references.pmid: 17051156
references.citation: Genes Dev. 2001 Jan 1;15(1):50-65
references.pmid: 11156605
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):245-55
references.pmid: 19230643
references.citation: Cancer Res. 2000 Nov 1;60(21):5934-6
references.pmid: 11085506
references.citation: Cell. 2010 Feb 5;140(3):384-96
references.pmid: 20096447
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: BJU Int. 2011 Feb;107(4):656-63
references.pmid: 20735391
references.citation: Mol Cell. 2005 Sep 2;19(5):607-18
references.pmid: 16137618
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6683-8
references.pmid: 10359772
references.citation: Methods Enzymol. 2006;409:524-40
references.pmid: 16793422
references.citation: J Cell Biochem. 2011 Dec;112(12):3856-62
references.pmid: 21845734
references.citation: Cancer Res. 2001 Jul 1;61(13):4990-3
references.pmid: 11431331
references.citation: Science. 1998 Sep 11;281(5383):1677-9
references.pmid: 9733515
references.citation: Breast Cancer Res Treat. 2010 Aug;123(1):139-47
references.pmid: 19921427
references.citation: Science. 2002 Nov 15;298(5597):1435-8
references.pmid: 12364621
references.citation: Nat Med. 2012 Oct;18(10):1511-7
references.pmid: 23001183
references.citation: Nat Struct Mol Biol. 2011 Jun;18(6):721-7
references.pmid: 21552262
references.citation: Science. 1998 Sep 11;281(5383):1674-7
references.pmid: 9733514
references.citation: Trends Pharmacol Sci. 2011 May;32(5):308-16
references.pmid: 21458083
references.citation: Genes Dev. 1999 Oct 15;13(20):2633-8
references.pmid: 10541549
references.citation: Breast Cancer Res Treat. 2013 Feb;138(1):81-90
references.pmid: 23412770
references.citation: Mol Cell. 2004 Mar 26;13(6):879-86
references.pmid: 15053880
references.citation: Adv Cancer Res. 2010;108:73-112
references.pmid: 21034966
references.citation: Science. 1995 Jun 23;268(5218):1749-53
references.pmid: 7792600
references.citation: Trends Mol Med. 2011 Feb;17(2):88-96
references.pmid: 21087899
references.citation: Genes Dev. 1998 Dec 15;12(24):3831-42
references.pmid: 9869637
references.citation: J Exp Med. 2011 May 9;208(5):875-83
references.pmid: 21518799
references.citation: Nat Cell Biol. 2011 Mar;13(3):317-23
references.pmid: 21336307
references.citation: Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):551-61
references.pmid: 16414371
references.citation: Cell. 2005 Dec 29;123(7):1213-26
references.pmid: 16377563
references.citation: Cancer Res. 2004 Oct 1;64(19):7144-9
references.pmid: 15466212
references.citation: Cancer Res. 2006 Apr 1;66(7):3893-902
references.pmid: 16585218
references.citation: Invest New Drugs. 2012 Dec;30(6):2113-20
references.pmid: 22127459
references.citation: Dev Cell. 2008 Jun;14(6):818-29
references.pmid: 18539112
references.citation: Lancet. 2005 Feb 19-25;365(9460):671-9
references.pmid: 15721472
references.citation: Nat Cell Biol. 2007 Apr;9(4):391-401
references.pmid: 17384638
references.citation: Nature. 2003 Feb 27;421(6926):961-6
references.pmid: 12607005
references.citation: Radiat Res. 1981 Sep;87(3):710-7
references.pmid: 7025087
references.citation: Nature. 2000 Nov 23;408(6811):433-9
references.pmid: 11100718
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Oncogene. 2010 Aug 26;29(34):4741-51
references.pmid: 20531305
references.citation: Mutat Res. 1998 Feb 26;398(1-2):101-10
references.pmid: 9626970
references.citation: J Biol Chem. 2004 Jan 16;279(3):2273-80
references.pmid: 14561744
references.citation: Breast. 2004 Dec;13(6):452-60
references.pmid: 15563851
references.citation: Nature. 2008 Oct 9;455(7214):813-7
references.pmid: 18716620
references.citation: Nat Rev Cancer. 2008 Jul;8(7):545-54
references.pmid: 18511937
references.citation: Mol Cell Biol. 1999 Dec;19(12):8581-90
references.pmid: 10567582
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1009-14
references.pmid: 15279787
references.citation: Cancer Cell. 2003 May;3(5):421-9
references.pmid: 12781359
references.citation: N Engl J Med. 2009 Jan 1;360(1):63-70
references.pmid: 19118305
references.citation: Development. 2008 Feb;135(3):579-88
references.pmid: 18192284
references.citation: Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):331-5
references.pmid: 14751500
references.citation: Nat Med. 2013 Sep;19(9):1104-9
references.pmid: 24013756
references.citation: RNA. 2003 Apr;9(4):493-501
references.pmid: 12649500
references.citation: Oncogene. 2012 Oct 25;31(43):4619-29
references.pmid: 22249256
references.citation: Nature. 2002 Apr 11;416(6881):648-53
references.pmid: 11923872
references.citation: Annu Rev Biochem. 2004;73:39-85
references.pmid: 15189136
references.citation: J Biol Chem. 1998 Mar 6;273(10):5858-68
references.pmid: 9488723
references.citation: Science. 1999 Nov 5;286(5442):1162-6
references.pmid: 10550055