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. Scardino & 5 others Michael J. Zelefsky, Maria Jasin, Jayanta Chaudhuri, Simon N. Powell, Charles L. Sawyers

Research output: Contribution to journalArticle

165 Citations (Scopus)

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

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Androgen Receptors
DNA Repair
Prostatic Neoplasms
Androgen Antagonists
Androgens
Genes
Ionizing Radiation
DNA Damage
Castration
Therapeutics
Radiotherapy
Down-Regulation
RNA

ASJC Scopus subject areas

  • Oncology

Cite this

Polkinghorn, W. R., Parker, J. S., Lee, M. X., Kass, E. M., Spratt, D. E., Iaquinta, P. 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

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

In: Cancer Discovery, Vol. 3, No. 11, 11.2013, p. 1245-1253.

Research output: Contribution to journalArticle

Polkinghorn, WR, Parker, JS, Lee, MX, Kass, EM, Spratt, DE, Iaquinta, PJ, Arora, VK, Yen, WF, Cai, L, Zheng, D, Carver, BS, Chen, Y, Watson, PA, Shah, NP, Fujisawa, S, Goglia, AG, Gopalan, A, Hieronymus, H, Wongvipat, J, Scardino, PT, Zelefsky, MJ, Jasin, M, Chaudhuri, J, Powell, SN & Sawyers, CL 2013, 'Androgen receptor signaling regulates DNA repair in prostate cancers', Cancer Discovery, vol. 3, no. 11, pp. 1245-1253. https://doi.org/10.1158/2159-8290.CD-13-0172
Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discovery. 2013 Nov;3(11):1245-1253. https://doi.org/10.1158/2159-8290.CD-13-0172
Polkinghorn, William R. ; Parker, Joel S. ; Lee, Man X. ; Kass, Elizabeth M. ; Spratt, Daniel E. ; Iaquinta, Phillip J. ; Arora, Vivek K. ; Yen, Wei Feng ; Cai, Ling ; Zheng, Deyou ; Carver, Brett S. ; Chen, Yu ; Watson, Philip A. ; Shah, Neel P. ; Fujisawa, Sho ; Goglia, Alexander G. ; Gopalan, Anuradha ; Hieronymus, Haley ; Wongvipat, John ; Scardino, Peter T. ; Zelefsky, Michael J. ; Jasin, Maria ; Chaudhuri, Jayanta ; Powell, Simon N. ; Sawyers, Charles L. / Androgen receptor signaling regulates DNA repair in prostate cancers. In: Cancer Discovery. 2013 ; Vol. 3, No. 11. pp. 1245-1253.
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