TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer
| Autor: | Robert G. Bristow, Theodorus van der Kwast, Ken Kron, Stanley Zhou, Vincent Huang, Michael Fraser, Mathieu Lupien, Takafumi N. Yamaguchi, Yu Jia Shiah, Paul C. Boutros, Alexander Murison |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Hepatocyte Nuclear Factor 3-alpha Male Oncogene Proteins Fusion Notch signaling pathway Biology Regulatory Sequences Nucleic Acid TMPRSS2 03 medical and health sciences Prostate cancer Transcriptional Regulator ERG Cell Movement Cell Line Tumor Genetics medicine Humans Transcription factor Regulation of gene expression Homeodomain Proteins Receptors Notch Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Serine Endopeptidases Prostatic Neoplasms medicine.disease Chromatin Gene Expression Regulation Neoplastic 030104 developmental biology Cancer research RNA Interference FOXA1 Erg Signal Transduction Transcription Factors |
| Zdroj: | Nature genetics. 49(9) |
| ISSN: | 1546-1718 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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