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

KJ Kron, A Murison, S Zhou, V Huang, TN Yamaguchi… - Nature …, 2017 - nature.com
Nature genetics, 2017nature.com
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 …
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.
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