Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation.

Journal Article (Journal Article)

Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy 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 radiotherapy 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. Furthermore, 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-induced NED and 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 radiotherapy.

Full Text

Duke Authors

Cited Authors

  • Owens, JL; Beketova, E; Liu, S; Shen, Q; Pawar, JS; Asberry, AM; Yang, J; Deng, X; Elzey, BD; Ratliff, TL; Cheng, L; Choo, R; Citrin, DE; Polascik, TJ; Wang, B; Huang, J; Li, C; Wan, J; Hu, C-D

Published Date

  • March 1, 2022

Published In

Volume / Issue

  • 21 / 3

Start / End Page

  • 448 - 459

PubMed ID

  • 35027481

Pubmed Central ID

  • PMC8898292

Electronic International Standard Serial Number (EISSN)

  • 1538-8514

Digital Object Identifier (DOI)

  • 10.1158/1535-7163.MCT-21-0103

Language

  • eng

Conference Location

  • United States