Abstract Prostate cancer remains the most frequently diagnosed cancer and the second leading cause of cancer-related death among men in the United States. We previously demonstrated that Polo-like kinase 1 (PLK1) phosphorylates PRMT5 at the S470 site, a modification required to maintain PRMT5 enzymatic activity and to promote DDR in prostate cancer cells. Here, we further uncover the functional consequences of this phosphorylation on cell cycle regulation and radiosensitivity. RNA-seq analysis revealed that PLK1-associated phosphorylation at S470 influences cell cycle-related pathways. Flow cytometry showed that the phospho-deficient PRMT5 mutant (S470A) accumulates in S and G2 phases compared to wild-type cells. Consistently, ChIP-qPCR analysis demonstrated increased binding of H4R3Me2s to genes inducing cell cycle arrest and decreased association with genes driving cell cycle progression in S470A cells. Importantly, both PLK1 inhibition (Onvansertib) and PRMT5 inhibition (Onametostat) synergized with ionizing radiation (IR) to suppress tumor growth in vitro and in vivo. These findings highlight a previously unrecognized role of PLK1-mediated PRMT5 phosphorylation in cell cycle control and radiosensitivity, suggesting that targeting the PLK1-PRMT5 axis may serve as a promising therapeutic strategy to enhance radiotherapy efficacy in prostate cancer. Citation Format: Jia Peng, Xinyi Wang, Daheng He, Jianlin Wang, Qianjin Li, Fatemeh Seilani, Xiongjian Rao, Meng Wu, Jinghui Liu, Ruixin Wang, Pingli Mo, Min Zhang, Sai Wu, Yanquan Zhang, Zhiguo Li, Izumi Tadahide, Xiaoqi Liu, . Targeting the PLK1-PRMT5 axis enhances radiosensitivity in prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6617.
Peng et al. (2026) studied this question.