TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer
Menée à l'aide de lignées cellulaires et d'échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, en présence d'une fusion des gènes TMPRSS2 et ERG, la surexpression de la protéine ERG induit, via des facteurs de transcription, une activation de la signalisation NOTCH
TMPRSS2-ERG (T2E) structural rearrangements typify [sim]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.