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Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis.

Publication ,  Journal Article
Lunardi, A; Varmeh, S; Chen, M; Taulli, R; Guarnerio, J; Ala, U; Seitzer, N; Ishikawa, T; Carver, BS; Hobbs, RM; Quarantotti, V; Ng, C ...
Published in: Cancer Discov
May 2015

UNLABELLED: The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members, such as ERG, ETV1, ETV4, and ETV5, are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here, we show that ETS family members, such as ERG and ETV1, directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA damage response cell-cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia into prostatic invasive carcinoma in Pten(+) (/-) mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications. SIGNIFICANCE: Genetic translocation and aberrant expression of ETS family members is a common event in different types of human tumors. Here, we show that through the transcriptional repression of CHK1, ETS factors may favor DNA damage accumulation and consequent genetic instability in proliferating cells. Importantly, our findings provide a rationale for testing DNA replication inhibitor agents in ETS-positive TP53-proficient tumors.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

May 2015

Volume

5

Issue

5

Start / End Page

550 / 563

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcriptional Regulator ERG
  • Transcription, Genetic
  • Transcription Factors
  • Trans-Activators
  • Proto-Oncogene Proteins c-ets
  • Protein Kinases
  • Protein Binding
  • Prostatic Neoplasms
  • Promoter Regions, Genetic
 

Citation

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Lunardi, A., Varmeh, S., Chen, M., Taulli, R., Guarnerio, J., Ala, U., … Pandolfi, P. P. (2015). Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer Discov, 5(5), 550–563. https://doi.org/10.1158/2159-8290.CD-13-1050
Lunardi, Andrea, Shohreh Varmeh, Ming Chen, Riccardo Taulli, Jlenia Guarnerio, Ugo Ala, Nina Seitzer, et al. “Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis.Cancer Discov 5, no. 5 (May 2015): 550–63. https://doi.org/10.1158/2159-8290.CD-13-1050.
Lunardi A, Varmeh S, Chen M, Taulli R, Guarnerio J, Ala U, et al. Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer Discov. 2015 May;5(5):550–63.
Lunardi, Andrea, et al. “Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis.Cancer Discov, vol. 5, no. 5, May 2015, pp. 550–63. Pubmed, doi:10.1158/2159-8290.CD-13-1050.
Lunardi A, Varmeh S, Chen M, Taulli R, Guarnerio J, Ala U, Seitzer N, Ishikawa T, Carver BS, Hobbs RM, Quarantotti V, Ng C, Berger AH, Nardella C, Poliseno L, Montironi R, Castillo-Martin M, Cordon-Cardo C, Signoretti S, Pandolfi PP. Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer Discov. 2015 May;5(5):550–563.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

May 2015

Volume

5

Issue

5

Start / End Page

550 / 563

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcriptional Regulator ERG
  • Transcription, Genetic
  • Transcription Factors
  • Trans-Activators
  • Proto-Oncogene Proteins c-ets
  • Protein Kinases
  • Protein Binding
  • Prostatic Neoplasms
  • Promoter Regions, Genetic