Nature genetics, 2017-09, Vol.49 (9), p.1336-1345
2017
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- Autor(en) / Beteiligte
- Titel
- TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer
- Ist Teil von
- Nature genetics, 2017-09, Vol.49 (9), p.1336-1345
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036eISSN: 1546-1718DOI: 10.1038/ng.3930Titel-ID: cdi_proquest_journals_1938055863
- Format
- –
- Schlagworte
- Androgens, Binding sites, Cancer, Cell growth, Cell Line, Tumor, Cell Movement - genetics, Cellular signal transduction, Chromatin, Cores, Development and progression, Gene expression, Gene Expression Profiling - methods, Gene Expression Regulation, Neoplastic, Gene loci, Genetic aspects, Genomes, Hepatocyte Nuclear Factor 3-alpha - genetics, Homeodomain Proteins - genetics, Humans, Male, Mutation, Notch protein, Oncogene Proteins, Fusion - genetics, Physiological aspects, Prostate cancer, Prostatic Neoplasms - genetics, Prostatic Neoplasms - pathology, Proteins, Receptors, Notch - genetics, Regulatory sequences, Regulatory Sequences, Nucleic Acid - genetics, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Serine Endopeptidases - genetics, Signal transduction, Signal Transduction - genetics, Transcription factors, Transcription Factors - genetics, Transcriptional Regulator ERG - genetics, Tumors