Prostate cancer remains the second leading cause of cancer death among American men. Radiation therapy (RT) is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly-aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical RT protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically-relevant model. Further, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-inhibited NED sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer RT.
Molecular cancer therapeutics. 2022 Jan 13 [Epub ahead of print]
Jake L Owens, Elena Beketova, Sheng Liu, Qi Shen, Jogendra Singh Pawar, Andrew M Asberry, Jie Yang, Xuehong Deng, Bennett D Elzey, Timothy L Ratliff, Liang Cheng, C Richard Choo, Deborah E Citrin, Thomas J Polascik, Bangchen Wang, Jiaoti Huang, Chenglong Li, Jun Wan, Chang-Deng Hu
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University West Lafayette., Department of Medical and Molecular Genetics, Indiana University School of Medicine., Medicinal Chemistry and Molecular Pharmacolog, Purdue University West Lafayette., Department of Comparative Pathobiology, Purdue University West Lafayette., Comparative Pathobiology and the Center for Cancer Research, Purdue University West Lafayette., Pathology and Laboratory Medicine, Indiana University School of Medicine., Radiation Oncology, Mayo Clinic., Radiation Oncology Branch, National Cancer Institute., Urologic Surgery, Duke Medical Center., Department of Pathology, Duke University School of Medicine., College of Pharmacy, University of Florida., Medical and Molecular Genetics, Indiana University School of Medicine., Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University West Lafayette .