Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis.
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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.
SubjectCell Line, Tumor
Cell Transformation, Neoplastic
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-ets
Promoter Regions, Genetic
Checkpoint Kinase 1
Transcriptional Regulator ERG
Published Version (Please cite this version)10.1158/2159-8290.CD-13-1050
Publication InfoLunardi, Andrea; Varmeh, Shohreh; Chen, Ming; Taulli, Riccardo; Guarnerio, Jlenia; Ala, Ugo; ... Pandolfi, Pier Paolo (2015). Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis. Cancer discovery, 5(5). pp. 550-563. 10.1158/2159-8290.CD-13-1050. Retrieved from https://hdl.handle.net/10161/20382.
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Assistant Professor in Pathology
Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long
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