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Cell death & disease
Apr 02, 2015;6 e1708.

Negative feedback loop between p66Shc and ZEB1 regulates fibrotic EMT response in lung cancer cells.

X Li, D Gao, H Wang, X Li, J Yang, X Yan, Z Liu, Z Ma
Author Information
  1. X Li: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Laboratory of Epigenetics and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  2. D Gao: Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
  3. H Wang: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Laboratory of Epigenetics and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  4. X Li: Department of Pharmaceutical Engineering, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China.
  5. J Yang: Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
  6. X Yan: Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
  7. Z Liu: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Laboratory of Epigenetics and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China [3] Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China [4] Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital, Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
  8. Z Ma: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital, Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
PMID: 25837484 DOI: 10.1038/cddis.2015.74

Abstract

The epithelial-to-mesenchymal transition (EMT) program is crucial for the epithelial cancer progression and fibrotic diseases. Our previous work has demonstrated that p66Shc, a focal adhesion-associated adaptor protein, is frequently downregulated in lung cancers and its depletion promotes metastasis behavior through anoikis resistance. However, mechanism underlying loss of p66Shc and EMT response is not fully understood. Here, we showed that p66Shc deficiency enhanced the expression of ZEB1, the known mesenchymal transcription factor and consequently increased Vimentin, and decreased epithelial markers of E-cadherin and β-catenin. p66Shc depletion also increased cell invasion and migration. In addition, ChIP and luciferase assays showed that these effects were directly mediated by ZEB1 repression of p66Shc promoter. Thus, our findings define a critical role of p66Shc in the suppression of fibrotic EMT response with a negative feedback loop between p66Shc and ZEB1 in lung epithelial cancer cells.

References

  1. Cancer Cell. 2014 May 12;25(5):575-89 [PMID: 24823637]
  2. J Cell Sci. 2013 Jan 1;126(Pt 1):21-9 [PMID: 23516327]
  3. Oncogene. 2015 Mar 26;34(13):1709-17 [PMID: 24747970]
  4. Cell. 2013 Jul 3;154(1):61-74 [PMID: 23827675]
  5. Cancer Lett. 2013 Aug 28;337(1):58-65 [PMID: 23689140]
  6. Nature. 1999 Nov 18;402(6759):309-13 [PMID: 10580504]
  7. Curr Opin Cell Biol. 2001 Oct;13(5):555-62 [PMID: 11544023]
  8. J Biol Chem. 2002 Jun 21;277(25):22370-6 [PMID: 11948181]
  9. Nat Rev Mol Cell Biol. 2004 Oct;5(10):816-26 [PMID: 15459662]
  10. Mol Biol Cell. 1993 Sep;4(9):953-61 [PMID: 8257797]
  11. J Cell Biol. 1994 Feb;124(4):619-26 [PMID: 8106557]
  12. EMBO J. 1997 Feb 17;16(4):706-16 [PMID: 9049300]
  13. Cancer Res. 2004 Dec 15;64(24):9027-34 [PMID: 15604268]
  14. Mol Cell Biol. 2005 Apr;25(8):3220-31 [PMID: 15798207]
  15. Cancer Res. 2005 Jul 15;65(14):5991-5; discussion 5995 [PMID: 16024595]
  16. Cell Death Differ. 2005 Nov;12 Suppl 2:1473-7 [PMID: 16247493]
  17. Cancer Metastasis Rev. 2005 Sep;24(3):425-39 [PMID: 16258730]
  18. Science. 2007 Jul 13;317(5835):251-6 [PMID: 17626887]
  19. J Cell Biol. 2007 Oct 8;179(1):23-31 [PMID: 17908916]
  20. Cell. 2008 May 16;133(4):704-15 [PMID: 18485877]
  21. Cancer Res. 2008 Jul 1;68(13):5104-12 [PMID: 18593909]
  22. Cancer Lett. 2008 Dec 18;272(2):177-85 [PMID: 18579285]
  23. Cancer Res. 2008 Dec 1;68(23):9574-7 [PMID: 19047131]
  24. J Clin Invest. 2009 Jun;119(6):1420-8 [PMID: 19487818]
  25. Biochim Biophys Acta. 2009 Dec;1796(2):293-308 [PMID: 19683560]
  26. Cell. 2009 Nov 25;139(5):871-90 [PMID: 19945376]
  27. Oxid Med Cell Longev. 2010 Mar-Apr;3(2):77-85 [PMID: 20716932]
  28. Oncogene. 2010 Aug 26;29(34):4741-51 [PMID: 20531305]
  29. Oncogene. 2010 Oct 14;29(41):5559-67 [PMID: 20676142]
  30. Oncogene. 2010 Oct 14;29(41):5556-8 [PMID: 20711240]
  31. Dev Cell. 2010 Dec 14;19(6):831-44 [PMID: 21145499]
  32. Oncogene. 2011 Sep 1;30(35):3735-44 [PMID: 21478908]
  33. Cell Death Differ. 2011 Oct;18(10):1628-39 [PMID: 21527937]
  34. Mol Cell Biol. 2011 Oct;31(19):4036-51 [PMID: 21746881]
  35. Nat Rev Cancer. 2012 Jun;12(6):425-36 [PMID: 22576165]
  36. Curr Opin Cell Biol. 2012 Oct;24(5):685-94 [PMID: 22835462]
  37. Curr Opin Oncol. 2013 Jan;25(1):76-84 [PMID: 23197193]
  38. FEBS J. 2013 Sep;280(18):4522-30 [PMID: 23815759]
  39. PLoS One. 2013;8(10):e76346 [PMID: 24098479]
  40. Curr Cancer Drug Targets. 2013 Nov;13(9):963-72 [PMID: 24168186]
  41. J Pathol. 2014 Feb;232(3):283-8 [PMID: 24254977]
  42. Nat Rev Mol Cell Biol. 2014 Mar;15(3):178-96 [PMID: 24556840]
  43. Cell Death Dis. 2014;5:e1092 [PMID: 24577090]
  44. Cancer Treat Rev. 2014 Jul;40(6):716-22 [PMID: 24759599]
  45. Nat Cell Biol. 2014 Jun;16(6):488-94 [PMID: 24875735]
  46. Trends Pharmacol Sci. 2014 Sep;35(9):479-88 [PMID: 25042456]
  47. Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):E3775-84 [PMID: 25157139]
  48. Sci Signal. 2014 Sep 30;7(345):ra91 [PMID: 25270257]
  49. Nat Rev Cancer. 2013 Feb;13(2):97-110 [PMID: 23344542]

MeSH Term

Cell Line, Tumor
Epithelial-Mesenchymal Transition
Feedback, Physiological
Hep G2 Cells
Homeodomain Proteins
Humans
Lung Neoplasms
Shc Signaling Adaptor Proteins
Src Homology 2 Domain-Containing, Transforming Protein 1
Transcription Factors
Zinc Finger E-box-Binding Homeobox 1

Chemicals

Homeodomain Proteins
SHC1 protein, human
Shc Signaling Adaptor Proteins
Src Homology 2 Domain-Containing, Transforming Protein 1
Transcription Factors
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 7

Word Cloud

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