Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer

J. Chad Brenner, Bushra Ateeq, Yong Li, Anastasia K. Yocum, Qi Cao, Irfan A. Asangani, Sonam Patel, Xiaoju Wang, Hallie Liang, Jindan Yu, Nallasivam Palanisamy, Javed Siddiqui, Wei Yan, Xuhong Cao, Rohit Mehra, Aaron Sabolch, Venkatesha Basrur, Robert J. Lonigro, Jun Yang, Scott A. TomlinsChristopher A. Maher, Kojo S J Elenitoba-Johnson, Maha Hussain, Nora M. Navone, Kenneth J. Pienta, Sooryanarayana Varambally, Felix Y. Feng, Arul M. Chinnaiyan*

*Corresponding author for this work

Research output: Contribution to journalArticle

292 Scopus citations

Abstract

Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.

Original languageEnglish (US)
Pages (from-to)664-678
Number of pages15
JournalCancer Cell
Volume19
Issue number5
DOIs
StatePublished - May 17 2011

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Brenner, J. C., Ateeq, B., Li, Y., Yocum, A. K., Cao, Q., Asangani, I. A., Patel, S., Wang, X., Liang, H., Yu, J., Palanisamy, N., Siddiqui, J., Yan, W., Cao, X., Mehra, R., Sabolch, A., Basrur, V., Lonigro, R. J., Yang, J., ... Chinnaiyan, A. M. (2011). Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer. Cancer Cell, 19(5), 664-678. https://doi.org/10.1016/j.ccr.2011.04.010