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

Publication ,  Journal Article
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 ...
Published in: Mol Cancer Ther
March 1, 2022

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.

Duke Scholars

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

March 1, 2022

Volume

21

Issue

3

Start / End Page

448 / 459

Location

United States

Related Subject Headings

  • Protein-Arginine N-Methyltransferases
  • Prostatic Neoplasms
  • Prostate
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Mice
  • Male
  • Humans
  • Cell Line, Tumor
  • Cell Differentiation
 

Citation

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Owens, J. L., Beketova, E., Liu, S., Shen, Q., Pawar, J. S., Asberry, A. M., … Hu, C.-D. (2022). Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation. Mol Cancer Ther, 21(3), 448–459. https://doi.org/10.1158/1535-7163.MCT-21-0103
Owens, Jake L., Elena Beketova, Sheng Liu, Qi Shen, Jogendra Singh Pawar, Andrew M. Asberry, Jie Yang, et al. “Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation.Mol Cancer Ther 21, no. 3 (March 1, 2022): 448–59. https://doi.org/10.1158/1535-7163.MCT-21-0103.
Owens JL, Beketova E, Liu S, Shen Q, Pawar JS, Asberry AM, et al. Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation. Mol Cancer Ther. 2022 Mar 1;21(3):448–59.
Owens, Jake L., et al. “Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation.Mol Cancer Ther, vol. 21, no. 3, Mar. 2022, pp. 448–59. Pubmed, doi:10.1158/1535-7163.MCT-21-0103.
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. Targeting Protein Arginine Methyltransferase 5 Suppresses Radiation-induced Neuroendocrine Differentiation and Sensitizes Prostate Cancer Cells to Radiation. Mol Cancer Ther. 2022 Mar 1;21(3):448–459.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

March 1, 2022

Volume

21

Issue

3

Start / End Page

448 / 459

Location

United States

Related Subject Headings

  • Protein-Arginine N-Methyltransferases
  • Prostatic Neoplasms
  • Prostate
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Mice
  • Male
  • Humans
  • Cell Line, Tumor
  • Cell Differentiation