PLCε knockdown enhances the radiosensitivity of castration‑resistant prostate cancer via the AR/PARP1/DNA‑PKcs axis

: Radiotherapy (RT) has been used as a therapeutic option for treatment of prostate cancer (PCa) for a number of years; however, patients frequently develop RT resistance, particularly in castration‑resistant PCa (CRPC), although the underlying mechanisms remain unknown. Understanding the underlying mechanism of RT resistance in CRPC may potentially highlight novel targets to improve therapeutic options for patients with PCa. In the present study, the expression levels of phospholipase Ce (PLCe), androgen receptor (AR) and DNA‑dependent protein kinase catalytic subunit (PKcs) were examined in PCa tissue samples and PCa cells, and the effects of PLCe knockdown on AR and DNA damage repair (DDR)‑related molecules were determined. The association between PLCe, AR and Poly (ADP‑ribose) polymerase 1 (PARP1), as well as their respective roles in radiation resistance, were assessed using gene knockdown and pharmaceutical inhibitors or activators. A chromatin immunoprecipitation assay was used to determine the epigenetic regulatory effects of PLCe on PARP1. Animal experiments were performed to assess whether the mechanisms observed in vitro could be replicated in vivo. The expression levels of PLCe, AR and DNA‑PKcs were significantly upregulated in PCa, particularly in CRPC. PLCe knockdown reduced the viability and increased apoptosis of cells subjected to radiation. Additionally, PLCe deficiency suppressed DDR progression by downregulating an AR and PARP1 positive feedback loop and the associated downstream molecules following radiation. PLCe depletion also increased the presence of histone H3 lysine 27 trimethylation in the PARP1 promoter region, suggesting increased methylation of the PARP1 gene and thus resulting in reduced expression of PARP1. In vivo, PLCe knockdown significantly potentiated the effects of radiation on tumor growth. Taken together, the results of the present study demonstrated that PLCe knockdown enhanced the radiosensitivity of CRPC by downregulating the AR/PARP1/DNA‑PKcs axis.