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

Abstract

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.

• Authors: Andrea Lunardi, Shohreh Varmeh, Ming Chen, Riccardo Taulli, Jlenia Guarnerio, Ugo Ala, Nina Seitzer, Tomoki Ishikawa, Brett S Carver, Robin M Hobbs, Valentina Quarantotti, Christopher Ng, Alice H Berger, Caterina Nardella, Laura Poliseno, Rodolfo Montironi, Mireia Castillo-Martin, Carlos Cordon-Cardo, Sabina Signoretti, Pier Paolo Pandolfi
• Journal: Cancer discovery (Cancer Discov) Vol. 5 Issue 5 Pg. 550-63 (May 2015) ISSN: 2159-8290 [Electronic] United States
• PMID: 25653093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• DNA-Binding Proteins
• ERG protein, human
• ETV1 protein, human
• Proto-Oncogene Proteins c-ets
• Trans-Activators
• Transcription Factors
• Transcriptional Regulator ERG
• Tumor Suppressor Protein p53
• Etoposide
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Binding Sites
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Checkpoint Kinase 1
• Conserved Sequence
• DNA Damage
• DNA-Binding Proteins (genetics, metabolism)
• Disease Progression
• Down-Regulation
• Drug Resistance, Neoplasm (genetics)
• Etoposide (pharmacology)
• Gene Expression Regulation, Neoplastic
• Genotype
• Humans
• Male
• Mice
• Mice, Knockout
• PTEN Phosphohydrolase (genetics, metabolism)
• Promoter Regions, Genetic
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• Protein Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-ets (metabolism)
• Trans-Activators (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Regulator ERG
• Tumor Suppressor Protein p53 (genetics, metabolism)