Abstract
There is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are key enzymes in BER that elongate and degrade PAR polymers on target proteins. While PARP inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the PARG locus and induces PARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. Thus, AR and PARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients.
Highlights
Poly(ADP-ribose) glycohydrolase (PARG) and PARP1 are key enzymes required for DNA repair and maintenance of genomic stability
In primary prostate cancer LuCaP35 xenografts tumors, intratumoral poly(ADP-ribose) glycohydrolase (PARG) expression declined in males 4 weeks after castration when compared to tumors from SHAM operated animals which underwent all surgical procedures except removal of the testicles [GSE33316] (Fig. 1e)
Based on the data generated by single cell sequencing of the normal human prostate, there was a significant overlap in androgen receptor (AR) and PARG expression in prostate epithelial compartments, further confirming the functional interaction between AR and PARG (Fig. 1kl)[33]
Summary
Poly(ADP-ribose) glycohydrolase (PARG) and PARP1 are key enzymes required for DNA repair and maintenance of genomic stability. Multiple PARPs synthesize PAR polymers, while the bulk of polymeric PAR is hydrolyzed by PARG via exo- and endo-glycosylase activities that generate mono (ADP-ribose) residues[8]. These mono (ADP-ribose) residues can be further hydrolyzed by ARH1, ARH3, and macrodomain proteins[9]. We found that inhibition of PARG synergized with androgen deprivation to reduce BER capacity and inhibit cellular proliferation and viability in multiple prostate cancer cell lines. We show that androgen receptor signaling stimulates DNA repair in part through increasing basal levels of PARG expression, suggesting a novel therapeutic target for prostate cancer patients with advanced disease
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