Journal Article

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

Fazli, Ladan, Gui, Fu, Liu, Shuai, Zhang, Wei, Jia, Li, Zhang, Xiaofeng, Kibel, Adam S., Dong, Xuesen, Bai, Xiao, Gui, Bin, Takai, Tomoaki, Feng, Chao

2019

Overview

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 transcriptionalmachinery 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.

• Publisher: National Academy of Sciences
• Subject: Adenosine diphosphate / Androgen receptors / Androgens / Animals / Antiandrogens / Benzimidazoles - pharmacology / Benzimidazoles - therapeutic use / Biochemistry / Biological Sciences / Castration / Catalysis / Catalytic activity / Cell Line, Tumor / Chemical compounds / Critical components / Datasets as Topic / Deoxyribonucleic acid / Disease-Free Survival / Disruption / DNA / DNA damage / DNA repair / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockout Techniques / Genomes / Hepatocyte Nuclear Factor 3-alpha - antagonists & inhibitors / Homologous recombination / Homology / Humans / Kaplan-Meier Estimate / Lethality / Ligands / Male / Mice / Pharmacology / Phthalazines - pharmacology / Phthalazines - therapeutic use / Piperazines - pharmacology / Piperazines - therapeutic use / PNAS Plus / Poly (ADP-Ribose) Polymerase-1 - genetics / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Poly(ADP-ribose) Polymerases - genetics / Poly(ADP-ribose) Polymerases - metabolism / Prostate - pathology / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - mortality / Prostatic Neoplasms, Castration-Resistant - pathology / Proteins / Receptors, Androgen - metabolism / Repair / Ribose / RNA, Small Interfering - metabolism / RNA-Seq / Signal Transduction - drug effects / Signal Transduction - genetics / Tissue Array Analysis / Tumors / Xenograft Model Antitumor Assays