Upregulation of PARG in prostate cancer cells suppresses their malignant behavior and downregulates tumor-promoting genes

Abstract

Post-translational modification of nuclear proteins through the addition of poly(ADP-ribose) (pADPr) moieties is upregulated in many metastatic cancers, where the high levels of pADPr have often been associated with poor cancer prognosis. Although the inhibitors of poly(ADP-ribose) polymerases (PARPs) have been utilized as potent anti-cancer agents, their efficacy in clinical trials varied among patient groups and has often been unpredictable. Such outcome cannot be interpreted solely by the inability to keep PARP-driven DNA repair in check. The focus of studies on PARP-driven tumorigenesis have recently been shifted toward PARP-dependent regulation of transcription. Here we utilized the controlled overexpression of poly(ADP-ribose) glycohydrolase (PARG), a sole pADPr-degrading enzyme, to investigate pADPr-dependent gene regulation in prostate cancer PC-3 cells. We demonstrated that PARG upregulation reduces pADPr levels and inhibits the expression of genes in key tumor-promoted pathways, including TNFα/NF-kB, IL6/STAT3, MYC, and KRAS signaling, the genes involved in inflammation response, especially chemokines, and endothelial-mesenchymal transition. The observed effect of PARG on transcription was consistent across all tested prostate cancer cell lines and correlates with PARG-induced reduction of clonogenic potential of PC-3 cells in vitro and a significant growth inhibition of PC-3-derived tumors in nude mice in vivo.