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

David Y. Takeda, Sándor Spisák, Ji Heui Seo, Connor Bell, Edward O'Connor, Keegan Korthauer, Dezső Ribli, István Csabai, Norbert Solymosi, Zoltán Szállási, David R. Stillman, Paloma Cejas, Xintao Qiu, Henry W. Long, Viktória Tisza, Pier Vitale Nuzzo, Mersedeh Rohanizadegan, Mark M. Pomerantz, William C. Hahn, Matthew L. Freedman

Research output: Contribution to journalArticle

44 Citations (Scopus)

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. Activation and amplification of an enhancer upstream of the androgen receptor locus drives progression of metastatic castration-resistant prostate cancer.

Original languageEnglish
Pages (from-to)422-432.e13
JournalCell
Volume174
Issue number2
DOIs
Publication statusPublished - Jul 12 2018

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Takeda, D. Y., Spisák, S., Seo, J. H., Bell, C., O'Connor, E., Korthauer, K., Ribli, D., Csabai, I., Solymosi, N., Szállási, Z., Stillman, D. R., Cejas, P., Qiu, X., Long, H. W., Tisza, V., Nuzzo, P. V., Rohanizadegan, M., Pomerantz, M. M., Hahn, W. C., & Freedman, M. L. (2018). A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. Cell, 174(2), 422-432.e13. https://doi.org/10.1016/j.cell.2018.05.037