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Cell. 2018 Jul 12;174(2):422-432.e13. doi: 10.1016/j.cell.2018.05.037. Epub 2018 Jun 14.

A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Pázmány P. s. 1A, Budapest 1117, Hungary.
6
Centre for Bioinformatics, University of Veterinary Medicine, István str. 2, Budapest 1078, Hungary.
7
Computational Health Informatics Program (CHIP) Boston Children's Hospital Harvard Medical School, Boston, MA 02215, USA; Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark; 2nd Department of Pathology, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest 1091, Hungary.
8
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Computational Health Informatics Program (CHIP) Boston Children's Hospital Harvard Medical School, Boston, MA 02215, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Internal Medicine, School of Medicine, University of Genoa, Genoa, Lgo R. Benzi 10, 16132, Italy.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
12
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: mfreedman@partners.org.

Abstract

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers.

KEYWORDS:

androgen receptor; castrate resistant; enhancer; epigenetic; epigenome editing; epigenomic; functional genomics; genome editing; prostate cancer

PMID:
29909987
PMCID:
PMC6046260
[Available on 2019-07-12]
DOI:
10.1016/j.cell.2018.05.037

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