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.

中文翻译：

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TMPRSS2-ERG融合可以共同选择主转录因子并激活原发性前列腺癌中的NOTCH信号传导。

TMPRSS2-ERG（T2E）结构重排代表约50％的前列腺肿瘤，并导致ERG转录因子的过表达。使用染色质，基因组和表达数据，我们显示了T2E阳性和非T2E原发性前列腺肿瘤之间的独特的顺式调控景观，其中包括调控元件（CORE）簇。这种差异是由HOXB13和FOXA1的ERG共同选择介导的，实现了T2E特异性的转录特征。我们还报告了一个T2E特异性CORE，该EORE基因在结构上已重新排列，这是由于TMPRSS2基因座先前存在的CORE扩散所致，有助于其过表达。最后，我们证明了T2E特异的顺式调控态势是对抗NOTCH途径的脆弱性的基础。确实，NOTCH通路抑制作用可拮抗T2E阳性前列腺癌细胞的生长和侵袭。