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PMID: 15314206 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Triplex DNA-mediated downregulation of Ets2 expression results in growth inhibition and apoptosis in human prostate cancer cells.

Nucleic acids research ·Vol. 32 ·No. 14 ·2004-00-00 ·Pages 4358-67

Carbone GM, Napoli S, Valentini A, Cavalli F, Watson DK, Catapano CV

Abstract

Ets2 is a member of the Ets family of transcription factors that in humans comprise 25 distinct members. Various Ets-domain transcription factors have been implicated in cancer development. Ets2 is expressed in prostate and breast cancer cells and is thought to have a role in promoting growth and survival in these cell types. However, a definitive role and the mechanisms whereby Ets2 acts in cancer cells are still unclear. Structural and functional similarities as well as overlapping DNA binding specificities complicate the identification of the specific roles of the various Ets factors. In this study, we used a triplex-forming oligonucleotide (TFO) to selectively inhibit Ets2 transcription in prostate cancer cells. We had previously shown that the Ets2-targeting TFO, which was directed to a unique purine-rich sequence critical for Ets2 promoter activity, acted with a high degree of sequence-specificity and target selectivity. TFO-mediated downregulation of Ets2 in prostate cancer cells induced important phenotypic changes, including inhibition of anchorage-dependent and anchorage -independent growth, cell cycle alterations and induction of apoptotic cell death. Expression of Ets2 under the control of a heterologous promoter abolished the anti-proliferative effects of the TFO in both short- and long-term assays, suggesting that these effects were a direct result of downregulation of Ets2 transcription and confirming target selectivity of the TFO. Furthermore, normal human fibroblasts, which expressed low levels of Ets2, were not affected by the Ets2-targeting TFO. Downregulation of Ets2 in prostate cancer cells was associated with reduced levels of the anti-apoptotic protein bcl-x(L) and growth regulatory factors cyclin D1 and c-myc. These data revealed a specific role of this transcription factor in promoting growth and survival of prostate cancer cells. Furthermore, the activity and selectivity of the Ets2-targeting TFO suggest that it might represent a valid approach to prostate cancer therapy.

MeSH Terms
Apoptosis Base Sequence Cell Cycle Cell Division Cell Line, Tumor DNA/genetics Down-Regulation Gene Expression Regulation Humans Male Molecular Sequence Data Prostatic Neoplasms/metabolism,pathology,therapy Proto-Oncogene Protein c-ets-2 Proto-Oncogene Proteins/antagonists & inhibitors,genetics,metabolism Trans-Activators/antagonists & inhibitors,genetics,metabolism
Chemicals
ETS2 protein, human Proto-Oncogene Protein c-ets-2 Proto-Oncogene Proteins Trans-Activators triplex DNA DNA
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Carbone Giuseppina M
Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Via Vela 6, 6500 Bellinzona, Switzerland. [email protected]
Napoli Sara
Valentini Alessandra
Cavalli Franco
Watson Dennis K
Catapano Carlo V
References (52)
52 references, click to expand
  1. Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1.
    Oncogene. 1994 Feb;9(2):405-15 PMID: 8290253
  2. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions.
    J Biol Chem. 1995 Oct 6;270(40):23589-97 PMID: 7559524
  3. Reversion of Ras transformed cells by Ets transdominant mutants.
    Oncogene. 1994 Dec;9(12):3665-73 PMID: 7970725
  4. Triplex DNA structures.
    Annu Rev Biochem. 1995;64:65-95 PMID: 7574496
  5. Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.
    Mol Cell Biol. 1996 Feb;16(2):538-47 PMID: 8552081
  6. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers.
    Am J Pathol. 1996 May;148(5):1567-76 PMID: 8623925
  7. Oncogenic Neu/ErbB-2 increases ets, AP-1, and NF-kappaB-dependent gene expression, and inhibiting ets activation blocks Neu-mediated cellular transformation.
    J Biol Chem. 1996 Apr 5;271(14):7992-8 PMID: 8626480
  8. Progress in antisense oligonucleotide therapeutics.
    Annu Rev Pharmacol Toxicol. 1996;36:107-29 PMID: 8725384
  9. Cancer cell cycles.
    Science. 1996 Dec 6;274(5293):1672-7 PMID: 8939849
  10. Temperature and salt dependence of higher order structure formation by antisense c-myc and c-myb phosphorothioate oligodeoxyribonucleotides containing tetraguanylate tracts.
    Nucleic Acids Res. 1997 Apr 1;25(7):1327-32 PMID: 9060425
  11. Identification of differentially expressed prostate genes: increased expression of transcription factor ETS-2 in prostate cancer.
    Prostate. 1997 Feb 15;30(3):145-53 PMID: 9122038
  12. Rapid phosphorylation of Ets-2 accompanies mitogen-activated protein kinase activation and the induction of heparin-binding epidermal growth factor gene expression by oncogenic Raf-1.
    Mol Cell Biol. 1997 May;17(5):2401-12 PMID: 9111309
  13. Triplex DNA: fundamentals, advances, and potential applications for gene therapy.
    J Mol Med (Berl). 1997 Apr;75(4):267-82 PMID: 9151213
  14. Formation of a G-tetrad and higher order structures correlates with biological activity of the RelA (NF-kappaB p65) 'antisense' oligodeoxynucleotide.
    Nucleic Acids Res. 1997 Jul 1;25(13):2648-56 PMID: 9185577
  15. Cell-cell interaction in prostate gene regulation and cytodifferentiation.
    Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10705-10 PMID: 9380699
  16. Ets-2 transdominant mutant abolishes anchorage-independent growth and macrophage colony-stimulating factor-stimulated invasion by BT20 breast carcinoma cells.
    Cancer Res. 1998 Mar 1;58(5):1027-33 PMID: 9500466
  17. Increased cell growth and tumorigenicity in human prostate LNCaP cells by overexpression to cyclin D1.
    Oncogene. 1998 Apr 16;16(15):1913-20 PMID: 9591774
  18. The molecular role of Myc in growth and transformation: recent discoveries lead to new insights.
    FASEB J. 1998 Jun;12(9):633-51 PMID: 9619443
  19. Ets transcription factors: nuclear effectors of the Ras-MAP-kinase signaling pathway.
    Trends Biochem Sci. 1998 Jun;23(6):213-6 PMID: 9644975
  20. Nucleic acid therapeutics: state of the art and future prospects.
    Blood. 1998 Aug 1;92(3):712-36 PMID: 9680338
  21. ETS2 function is required to maintain the transformed state of human prostate cancer cells.
    Oncogene. 1998 Dec 3;17(22):2883-8 PMID: 9879994
  22. The Ets2 transcription factor inhibits apoptosis induced by colony-stimulating factor 1 deprivation of macrophages through a Bcl-xL-dependent mechanism.
    Mol Cell Biol. 1999 Apr;19(4):2624-34 PMID: 10082528
  23. Triple helix formation and the antigene strategy for sequence-specific control of gene expression.
    Biochim Biophys Acta. 1999 Dec 10;1489(1):181-206 PMID: 10807007
  24. Overexpression of cyclin D1 is associated with metastatic prostate cancer to bone.
    Clin Cancer Res. 2000 May;6(5):1891-5 PMID: 10815912
  25. Inhibition of gene expression and cell proliferation by triple helix-forming oligonucleotides directed to the c-myc gene.
    Biochemistry. 2000 May 2;39(17):5126-38 PMID: 10819980
  26. Antigene and antiproliferative effects of a c-myc-targeting phosphorothioate triple helix-forming oligonucleotide in human leukemia cells.
    Cancer Res. 2000 Jul 15;60(14):3790-9 PMID: 10919652
  27. Altered Ets transcription factor activity in prostate tumor cells inhibits anchorage-independent growth, survival, and invasiveness.
    Oncogene. 2000 Nov 16;19(48):5507-16 PMID: 11114728
  28. Signal transduction and the Ets family of transcription factors.
    Oncogene. 2000 Dec 18;19(55):6503-13 PMID: 11175366
  29. Ets target genes: past, present and future.
    Oncogene. 2000 Dec 18;19(55):6533-48 PMID: 11175369
  30. Gene targeted agents: new opportunities for rational drug development.
    Curr Opin Mol Ther. 2000 Dec;2(6):670-81 PMID: 11249745
  31. Induction of ETS-1 and ETS-2 transcription factors is required for thyroid cell transformation.
    Cancer Res. 2001 Mar 1;61(5):2267-75 PMID: 11280797
  32. The ETS-domain transcription factor family.
    Nat Rev Mol Cell Biol. 2001 Nov;2(11):827-37 PMID: 11715049
  33. Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide.
    Nucleic Acids Res. 2003 Feb 1;31(3):833-43 PMID: 12560478
  34. Molecular biology of the Ets family of transcription factors.
    Gene. 2003 Jan 16;303:11-34 PMID: 12559563
  35. Prostate cancer epidemiology.
    Lancet. 2003 Mar 8;361(9360):859-64 PMID: 12642065
  36. Prostate cancer: a dynamic illness with shifting targets.
    Lancet Oncol. 2003 Jul;4(7):407-14 PMID: 12850191
  37. Prostate cancer.
    N Engl J Med. 2003 Jul 24;349(4):366-81 PMID: 12878745
  38. The potential for gene repair via triple helix formation.
    J Clin Invest. 2003 Aug;112(4):487-94 PMID: 12925687
  39. Specificity of cyclin D1 for androgen receptor regulation.
    Cancer Res. 2003 Aug 15;63(16):4903-13 PMID: 12941814
  40. Therapeutic modulation of endogenous gene function by agents with designed DNA-sequence specificities.
    Nucleic Acids Res. 2003 Nov 1;31(21):6064-78 PMID: 14576293
  41. Ets2-dependent stromal regulation of mouse mammary tumors.
    Mol Cell Biol. 2003 Dec;23(23):8614-25 PMID: 14612405
  42. Myc confers androgen-independent prostate cancer cell growth.
    J Clin Invest. 2003 Dec;112(11):1724-31 PMID: 14660748
  43. Triplex-forming oligonucleotide target sequences in the human genome.
    Nucleic Acids Res. 2004;32(1):354-60 PMID: 14726484
  44. G-rich oligonucleotide inhibits the binding of a nuclear protein to the Ki-ras promoter and strongly reduces cell growth in human carcinoma pancreatic cells.
    Biochemistry. 2004 Mar 9;43(9):2512-23 PMID: 14992588
  45. Ets proteins in biological control and cancer.
    J Cell Biochem. 2004 Apr 1;91(5):896-903 PMID: 15034925
  46. siRNAs: applications in functional genomics and potential as therapeutics.
    Nat Rev Drug Discov. 2004 Apr;3(4):318-29 PMID: 15060527
  47. DNA binding and antigene activity of a daunomycin-conjugated triplex-forming oligonucleotide targeting the P2 promoter of the human c-myc gene.
    Nucleic Acids Res. 2004;32(8):2396-410 PMID: 15121897
  48. c-ets-2 protooncogene has mitogenic and oncogenic activity.
    Proc Natl Acad Sci U S A. 1989 Oct;86(20):7833-7 PMID: 2813360
  49. The c-ets-1 proto-oncogene has oncogenic activity and is positively autoregulated.
    Oncogene. 1990 Dec;5(12):1761-7 PMID: 2284095
  50. Antiproliferative activity of G-rich oligonucleotides correlates with protein binding.
    J Biol Chem. 1999 Sep 10;274(37):26369-77 PMID: 10473594
  51. A single targeted Ets2 allele restricts development of mammary tumors in transgenic mice.
    Cancer Res. 1999 Sep 1;59(17):4242-6 PMID: 10485465
  52. Oncogenic Ras can induce transcriptional activation through a variety of promoter elements, including tandem c-Ets-2 binding sites.
    Oncogene. 1994 Oct;9(10):2913-21 PMID: 8084596
Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/gkh744
Email
[email protected]
Published
2004-00-00
Epub
2004-00-16
Pages
4358-67
Language
English
Region
England
NLM ID
0411011
PMCID
PMC514370
Subset
IM
Grants
NCI NIH HHS · CA-70735 · United States
External Links
PubMed source DOI: 10.1093/nar/gkh744 PMC Full Text View journal details
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