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Nat Genet. 2017 Sep;49(9):1336-1345. doi: 10.1038/ng.3930. Epub 2017 Aug 7.

TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer.

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
2
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
3
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
4
Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
5
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
6
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

Abstract

TMPRSS2-ERG (T2E) structural rearrangements typify ∼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.

PMID:
28783165
DOI:
10.1038/ng.3930
[Indexed for MEDLINE]

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