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PMID: 20562906 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells.

Oncogene ·Vol. 29 ·No. 33 ·2010-08-19 ·Pages 4658-70

Wang Y, Ngo VN, Marani M, Yang Y, Wright G, Staudt LM, Downward J

Abstract

Activating mutations in the KRAS gene are among the most prevalent genetic changes in human cancers. To identify synthetic lethal interactions in cancer cells harbouring mutant KRAS, we performed a large-scale screen in isogenic paired colon cancer cell lines that differ by a single allele of mutant KRAS using an inducible short hairpin RNA interference library. Snail2, a zinc finger transcriptional repressor encoded by the SNAI2 gene, was found to be selectively required for the long-term survival of cancer cells with mutant KRAS that have undergone epithelial-mesenchymal transition (EMT), a transdifferentiation event that is frequently seen in advanced tumours and is promoted by RAS activation. Snail2 expression is regulated by the RAS pathway and is required for EMT. Our findings support Snail2 as a possible target for the treatment of the broad spectrum of human cancers of epithelial origin with mutant RAS that have undergone EMT and are characterized by a high degree of chemoresistance and radioresistance.

MeSH Terms
Cell Line, Tumor Cell Transformation, Neoplastic/genetics,metabolism Colorectal Neoplasms/genetics,metabolism,therapy Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Genes, ras HCT116 Cells Humans Proto-Oncogene Proteins/genetics Proto-Oncogene Proteins p21(ras) Signal Transduction Snail Family Transcription Factors Transcription Factors/biosynthesis,genetics,metabolism Zinc Fingers/genetics ras Proteins/genetics,metabolism
Chemicals
KRAS protein, human Proto-Oncogene Proteins SNAI1 protein, human SNAI2 protein, human Snail Family Transcription Factors Transcription Factors Proto-Oncogene Proteins p21(ras) ras Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Wang Y
Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK.
Ngo V N
Marani M
Yang Y
Wright G
Staudt L M
Downward J
References (50)
50 references, click to expand
  1. Short interfering RNA directed against the SLUG gene increases cell death induction in human melanoma cell lines exposed to cisplatin and fotemustine.
    Cell Oncol. 2007;29(4):279-87 PMID: 17641412
  2. Requirement of the Akt/beta-catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug.
    Am J Pathol. 2009 Jun;174(6):2107-15 PMID: 19389926
  3. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions.
    J Biol Chem. 2003 Jun 6;278(23):21113-23 PMID: 12665527
  4. Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura.
    Genetics. 1946 May;31:269-90 PMID: 20985721
  5. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma.
    Cell. 2005 Nov 18;123(4):641-53 PMID: 16286009
  6. Slug (SNAI2) down-regulation by RNA interference facilitates apoptosis and inhibits invasive growth in neuroblastoma preclinical models.
    Clin Cancer Res. 2008 Jul 15;14(14):4622-30 PMID: 18628477
  7. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.
    Cell. 2009 May 29;137(5):821-34 PMID: 19490892
  8. Function of the zinc-finger transcription factor SNAI2 in cancer and development.
    Annu Rev Genet. 2007;41:41-61 PMID: 17550342
  9. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients.
    Br J Cancer. 2006 Jun 19;94(12):1816-22 PMID: 16773075
  10. The SLUG zinc-finger protein represses E-cadherin in breast cancer.
    Cancer Res. 2002 Mar 15;62(6):1613-8 PMID: 11912130
  11. Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription factor slug.
    Oncogene. 2007 Feb 22;26(8):1222-30 PMID: 16924233
  12. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways.
    Oncogene. 2005 Nov 14;24(50):7443-54 PMID: 16288291
  13. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival.
    Cancer Cell. 2009 Jun 2;15(6):489-500 PMID: 19477428
  14. Snail/slug family of repressors: slowly going into the fast lane of development and cancer.
    Gene. 2000 Oct 17;257(1):1-12 PMID: 11054563
  15. Integrating genetic approaches into the discovery of anticancer drugs.
    Science. 1997 Nov 7;278(5340):1064-8 PMID: 9353181
  16. Targeting RAS signalling pathways in cancer therapy.
    Nat Rev Cancer. 2003 Jan;3(1):11-22 PMID: 12509763
  17. The Slug gene is not essential for mesoderm or neural crest development in mice.
    Dev Biol. 1998 Jun 15;198(2):277-85 PMID: 9659933
  18. A molecular signature for Epithelial to Mesenchymal transition in a human colon cancer cell system is revealed by large-scale microarray analysis.
    Clin Exp Metastasis. 2009;26(6):569-87 PMID: 19340593
  19. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?
    Nat Rev Cancer. 2007 Jun;7(6):415-28 PMID: 17508028
  20. Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs.
    Oncol Rep. 2005 Oct;14(4):1083-6 PMID: 16142376
  21. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation.
    Nat Genet. 2005 Oct;37(10):1047-54 PMID: 16142232
  22. Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells.
    Oncogene. 2004 Nov 1;23(51):8376-83 PMID: 15517019
  23. The snail superfamily of zinc-finger transcription factors.
    Nat Rev Mol Cell Biol. 2002 Mar;3(3):155-66 PMID: 11994736
  24. shRNA libraries and their use in cancer genetics.
    Nat Methods. 2006 Sep;3(9):701-6 PMID: 16929315
  25. IRF4 addiction in multiple myeloma.
    Nature. 2008 Jul 10;454(7201):226-31 PMID: 18568025
  26. Complex networks orchestrate epithelial-mesenchymal transitions.
    Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42 PMID: 16493418
  27. E-cadherin is regulated by the transcriptional repressor SLUG during Ras-mediated transformation of intestinal epithelial cells.
    Surgery. 2005 Aug;138(2):306-12 PMID: 16153441
  28. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras.
    Science. 1993 Apr 2;260(5104):85-8 PMID: 8465203
  29. Ras oncogenes: split personalities.
    Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31 PMID: 18568040
  30. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition.
    Cancer Res. 2005 Oct 15;65(20):9455-62 PMID: 16230409
  31. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress.
    Mol Cell Biol. 2004 Sep;24(17):7559-66 PMID: 15314165
  32. Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers.
    Front Biosci (Landmark Ed). 2009 Jan 01;14:3035-50 PMID: 19273255
  33. Snail and slug play distinct roles during breast carcinoma progression.
    Clin Cancer Res. 2006 Sep 15;12(18):5395-402 PMID: 17000672
  34. Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells.
    Oncogene. 2004 Sep 23;23(44):7345-54 PMID: 15286702
  35. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells.
    Genes Dev. 1996 Oct 1;10(19):2462-77 PMID: 8843198
  36. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug.
    Oncogene. 2003 Jul 3;22(27):4205-11 PMID: 12833143
  37. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug.
    Nat Cell Biol. 2009 Jun;11(6):694-704 PMID: 19448627
  38. Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses.
    Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20864-9 PMID: 19106301
  39. Epidermal Ras blockade demonstrates spatially localized Ras promotion of proliferation and inhibition of differentiation.
    Oncogene. 2002 Feb 28;21(10):1527-38 PMID: 11896581
  40. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo.
    Cancer Cell. 2002 Oct;2(4):279-88 PMID: 12398892
  41. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.
    Cell. 2009 May 29;137(5):835-48 PMID: 19490893
  42. Molecular requirements for epithelial-mesenchymal transition during tumor progression.
    Curr Opin Cell Biol. 2005 Oct;17(5):548-58 PMID: 16098727
  43. A loss-of-function RNA interference screen for molecular targets in cancer.
    Nature. 2006 May 4;441(7089):106-10 PMID: 16572121
  44. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells.
    Genes Dev. 2000 Oct 15;14(20):2610-22 PMID: 11040215
  45. SLUG in cancer development.
    Oncogene. 2005 Apr 28;24(19):3073-82 PMID: 15735690
  46. The concept of synthetic lethality in the context of anticancer therapy.
    Nat Rev Cancer. 2005 Sep;5(9):689-98 PMID: 16110319
  47. Utilizing RNA interference to enhance cancer drug discovery.
    Nat Rev Drug Discov. 2007 Jul;6(7):556-68 PMID: 17599085
  48. Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK.
    J Cell Biol. 2003 Nov 24;163(4):847-57 PMID: 14623871
  49. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells.
    Stem Cells. 2009 Sep;27(9):2059-68 PMID: 19544473
  50. SnapShot: Ras Signaling.
    Cell. 2008 Jun 27;133(7):1292-1292.e1 PMID: 18585361
Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2010.218
Published
2010-08-19
Epub
2010-00-21
Pages
4658-70
Language
English
Region
England
NLM ID
8711562
PMCID
PMC7646260
Subset
IM
Grants
Intramural NIH HHS · Z01 BC011008 · United States
Cancer Research UK · United Kingdom
External Links
PubMed source DOI: 10.1038/onc.2010.218 PMC Full Text View journal details
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