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The Role of PARP2 in Prostate Cancer

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Brigham and Womens Hospital Boston United States

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Androgen receptor AR is a key driver of prostate cancer PCa growth and progression. Understanding the factors influencing AR-mediatedgene expression provides new opportunities for therapeutic intervention. PolyADP-ribose Polymerase PARP is a family of enzymes, which post-translationally modify a range of proteins and regulate many different cellular processes. PARP1 and PARP2 are two well-characterizedPARP 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 with homologous recombination DNA-repair deficiency. Here, we show that beyond DNA damage repair function, PARP2, but not PARP1, 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 PARP2 expression at both mRNA and protein levels show significantly higher expression of PARP2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer tumors. Selective targeting of PARP2 by genetic or pharmacological means blocks interaction between PARP2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits PCa growth. Next-generation anti-androgens act through inhibiting androgen synthesis or blocking ligand binding. Selective targeting of PARP2, 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.

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Technical Report,01 Jul 2018,30 Jun 2019



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Approved For Public Release;

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