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

• Published in: Nature genetics Vol. 49; no. 9; pp. 1336 - 1345
• Main Authors: Kron, Ken J, Murison, Alexander, Zhou, Stanley, Huang, Vincent, Yamaguchi, Takafumi N, Shiah, Yu-Jia, Fraser, Michael, van der Kwast, Theodorus, Boutros, Paul C, Bristow, Robert G, Lupien, Mathieu
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2017; Nature Publishing Group
• Subjects: 13/106; 45; 45/15; 45/70; 45/77; 631/337/176; 631/337/2019; 631/67/589/466; 96/106; Agriculture; Androgens; Animal Genetics and Genomics; Binding sites; Biomedicine; Cancer Research; Cell growth; Cell Line, Tumor; Cell Movement - genetics; Cellular signal transduction; Chromatin; Development and progression; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene Function; Gene loci; Genetic aspects; Genomes; Hepatocyte Nuclear Factor 3-alpha - genetics; Homeodomain Proteins - genetics; Human 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; Canada
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3930

Mathieu Lupien and colleagues analyze data from primary prostate tumors with and without
TMPRSS2–ERG
(T2E) rearrangements. They find that in T2E tumors, there is a distinct regulatory landscape resulting from the co-option of transcription factors by ERG which causes dependency on NOTCH signaling.
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.