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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Jun 19

PMID 29909987

Citations 175

Authors

David Y Takeda

Sandor Spisak

Ji-Heui Seo

Connor Bell

Edward OConnor

Keegan Korthauer

Dezso Ribli

Istvan Csabai

Norbert Solymosi

Zoltan Szallasi

David R Stillman

Paloma Cejas

Xintao Qiu

Henry W Long

Viktoria Tisza

Pier Vitale Nuzzo

Mersedeh Rohanizadegan

Mark M Pomerantz

William C Hahn

Matthew L Freedman

Affiliations

Soon will be listed here.

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.

Citing Articles

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