Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2019 Jul 16;116(29):14573-14582. doi: 10.1073/pnas.1908547116. Epub 2019 Jul 2.

Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function.

Author information

1
Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
2
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
3
Department of Chemistry, University of Massachusetts Boston, Boston, MA 02125.
4
Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; akibel@bwh.harvard.edu ljia@bwh.harvard.edu.

Abstract

Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.

KEYWORDS:

FOXA1; PARP inhibitor; PARP-2; androgen receptor; prostate cancer

PMID:
31266892
PMCID:
PMC6642419
[Available on 2020-01-02]
DOI:
10.1073/pnas.1908547116

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center