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

doi:10.1038/ng.3930

. 2017 Sep;49(9):1336-1345.

doi: 10.1038/ng.3930. Epub 2017 Aug 7.

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

Ken J Kron¹, Alexander Murison¹, Stanley Zhou^{1

2}, Vincent Huang³, Takafumi N Yamaguchi³, Yu-Jia Shiah³, Michael Fraser¹, Theodorus van der Kwast⁴, Paul C Boutros^{2

3

5}, Robert G Bristow^{1

2

6}, Mathieu Lupien^{1

2

3}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
³ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁴ Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
⁵ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

PMID: 28783165
DOI: 10.1038/ng.3930

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

Ken J Kron et al. Nat Genet. 2017 Sep.

. 2017 Sep;49(9):1336-1345.

doi: 10.1038/ng.3930. Epub 2017 Aug 7.

Authors

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
³ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁴ Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
⁵ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

PMID: 28783165
DOI: 10.1038/ng.3930

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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Comment in

Prostate cancer: Mastering transcription: TMPRSS2-ERG and the cis-regulatory landscape.
Stone L. Stone L. Nat Rev Urol. 2017 Oct;14(10):579. doi: 10.1038/nrurol.2017.141. Epub 2017 Aug 31. Nat Rev Urol. 2017. PMID: 28858334 No abstract available.
Re: Ken J. Kron, Alexander Murison, Stanley Zhou, et al. TMPRSS2-ERG Fusion Co-opts Master Transcription Factors and Activates NOTCH Signaling in Primary Prostate Cancer. Nat Genet 2017;49:1336-45.
Lavorgna G, Montorsi F, Salonia A. Lavorgna G, et al. Eur Urol. 2018 Apr;73(4):e106-e107. doi: 10.1016/j.eururo.2017.10.034. Epub 2017 Nov 10. Eur Urol. 2018. PMID: 29129399 No abstract available.

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[1] Am J Surg Pathol. 2007 Jun;31(6):882-8 - PubMed

[2] Am J Surg Pathol. 2007 Jun;31(6):882-8 - PubMed

[3] Elife. 2015 Nov 21;4:e10870 - PubMed

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[5] Cell. 2013 Nov 7;155(4):934-47 - PubMed

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[8] Nat Commun. 2016 Sep 28;7:12983 - PubMed

[9] Nature. 2011 Feb 10;470(7333):214-20 - PubMed

[10] Nature. 2011 Feb 10;470(7333):214-20 - PubMed

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

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

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