Androgen receptor signaling regulates DNA repair in prostate cancers

William R. Polkinghorn, Joel S. Parker, Man X. Lee, Elizabeth M. Kass, Daniel E. Spratt, Phillip J. Iaquinta, Vivek K. Arora, Wei Feng Yen, Ling Cai, Deyou Zheng, Brett S. Carver, Yu Chen, Philip A. Watson, Neel P. Shah, Sho Fujisawa, Alexander G. Goglia, Anuradha Gopalan, Haley Hieronymus, John Wongvipat, Peter T. ScardinoMichael J. Zelefsky, Maria Jasin, Jayanta Chaudhuri, Simon N. Powell, Charles L. Sawyers

Research output: Contribution to journalArticle

202 Scopus citations

Abstract

We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining. SIGNIFICANCE: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.

Original languageEnglish (US)
Pages (from-to)1245-1253
Number of pages9
JournalCancer discovery
Volume3
Issue number11
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Androgen receptor signaling regulates DNA repair in prostate cancers'. Together they form a unique fingerprint.

  • Cite this

    Polkinghorn, W. R., Parker, J. S., Lee, M. X., Kass, E. M., Spratt, D. E., Iaquinta, P. J., Arora, V. K., Yen, W. F., Cai, L., Zheng, D., Carver, B. S., Chen, Y., Watson, P. A., Shah, N. P., Fujisawa, S., Goglia, A. G., Gopalan, A., Hieronymus, H., Wongvipat, J., ... Sawyers, C. L. (2013). Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer discovery, 3(11), 1245-1253. https://doi.org/10.1158/2159-8290.CD-13-0172