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

Andrea Lunardi1, Shohreh Varmeh1, Ming Chen1

  • 1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Cancer Discovery
|February 6, 2015
PubMed
Abstract

Insights

ETS factors like ERG repress checkpoint kinase 1 (CHK1) in prostate cancer, promoting tumor growth. Downregulating CHK1 sensitizes tumors to etoposide, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ETS transcription factors are frequently overexpressed in prostate cancer due to chromosomal translocations.
  • The precise mechanisms by which ETS factors drive prostate tumorigenesis are not fully understood.

Purpose of the Study:

  • To investigate the role of ETS family members in regulating DNA damage response pathways in prostate cancer.
  • To identify functional targets of ETS factors involved in prostate tumorigenesis.

Main Methods:

  • Analysis of CHK1 expression in relation to ERG expression in human prostate cancer patients.
  • Utilizing a Pten(+/-) mouse model to study the in vivo effects of Chk1 heterozygosity on prostate cancer progression.
  • Evaluating the sensitivity of prostate tumor cells with downregulated CHK1 to etoposide and docetaxel treatments.

Main Results:

  • ETS family members, including ERG and ETV1, were found to directly repress the expression of checkpoint kinase 1 (CHK1).
  • ERG expression positively correlated with CHK1 downregulation in human prostate cancer.
  • Chk1 heterozygosity accelerated the progression of prostatic intraepithelial neoplasia to invasive carcinoma in mice.
  • CHK1 downregulation rendered prostate tumor cells sensitive to etoposide but not docetaxel.

Conclusions:

  • ETS factors contribute to prostate tumorigenesis by transcriptionally repressing CHK1, a key regulator of DNA damage response and genome integrity.
  • CHK1 downregulation by ETS factors may lead to DNA damage accumulation and genetic instability.
  • These findings support the testing of DNA replication inhibitors in ETS-positive, TP53-proficient tumors.

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