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.
Type
Journal articleSubject
Cell Line, TumorAnimals
Mice, Knockout
Humans
Mice
Prostatic Neoplasms
Cell Transformation, Neoplastic
DNA Damage
Disease Progression
Etoposide
Protein Kinases
DNA-Binding Proteins
Trans-Activators
Transcription Factors
Transcription, Genetic
Down-Regulation
Gene Expression Regulation, Neoplastic
Binding Sites
Conserved Sequence
Protein Binding
Drug Resistance, Neoplasm
Genotype
Male
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-ets
PTEN Phosphohydrolase
Promoter Regions, Genetic
Checkpoint Kinase 1
Transcriptional Regulator ERG
Permalink
https://hdl.handle.net/10161/20382Published Version (Please cite this version)
10.1158/2159-8290.CD-13-1050Publication Info
Lunardi, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Ming Chen
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

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
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