期刊
NATURE GENETICS
卷 49, 期 9, 页码 1336-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.3930
关键词
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资金
- Prostate Cancer Canada
- Movember Foundation [RS2014-04, RS2014-01]
- Ontario Institute for Cancer Research - Government of Ontario
- Princess Margaret Cancer Foundation
- Radiation Medicine Program Academic Enrichment Fund
- Canadian Breast Cancer Foundation (CBCF) postdoctoral fellowship
- Terry Fox Research Institute New Investigator Award
- Canadian Institute of Health Research (CIHR) New Investigator Award
- Canadian Cancer Society Research Scientist Award
- Investigator Award from the Ontario Institute for Cancer Research
- CIHR New Investigator Award
- Movember Rising Star Award from Prostate Cancer Canada
TMPRSS2-ERG (T2E) structural rearrangements typify similar to 50% of prostate tumors and result in overexpression of the ERG transcription factor. Using chromatin, genomic and expression data, we show distinct cis-regulatory landscapes between T2E-positive and non-T2E primary prostate tumors, which include clusters of regulatory elements (COREs). This difference is mediated by ERG co-option of HOXB13 and FOXA1, implementing a T2E-specific transcriptional profile. We also report a T2E-specific CORE on the structurally rearranged ERG locus arising from spreading of the TMPRSS2 locus pre-existing CORE, assisting in its overexpression. Finally, we show that the T2E-specific cis-regulatory landscape underlies a vulnerability against the NOTCH pathway. Indeed, NOTCH pathway inhibition antagonizes the growth and invasion of T2E-positive prostate cancer cells. Taken together, our work shows that overexpressed ERG co-opts master transcription factors to deploy a unique cis-regulatory landscape, inducing a druggable dependency on NOTCH signaling in T2E-positive prostate tumors.
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