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Cell DOI:10.1016/j.cell.2018.05.037

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

Publication TypeJournal Article
Year of Publication2018
AuthorsTakeda, DY, Spisák, S, Seo, J-H, Bell, C, O'Connor, E, Korthauer, K, Ribli, D, Csabai, I, Solymosi, N, Szallasi, Z, Stillman, DR, Cejas, P, Qiu, X, Long, HW, Tisza, V, Nuzzo, PVitale, Rohanizadegan, M, Pomerantz, MM, Hahn, WC, Freedman, ML
JournalCell
Volume174
Issue2
Pages422-432.e13
Date Published2018 07 12
ISSN1097-4172
KeywordsAcetylation, Adult, Aged, Antineoplastic Agents, Benzamides, Cell Line, Tumor, Cell Survival, CRISPR-Cas Systems, DNA Methylation, Enhancer Elements, Genetic, Gene Editing, Histones, Humans, Male, Middle Aged, Neoplasm Metastasis, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen
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.

DOI10.1016/j.cell.2018.05.037
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29909987?dopt=Abstract

Alternate JournalCell
PubMed ID29909987
PubMed Central IDPMC6046260
Grant ListR01 GM107427 / GM / NIGMS NIH HHS / United States
R01 CA193910 / CA / NCI NIH HHS / United States
K08 CA218530 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
R01 HG005220 / HG / NHGRI NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
R01 CA204954 / CA / NCI NIH HHS / United States