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Somasekharan SP, Saxena N, Zhang F, et al. Regulation of AR mRNA translation in response to acute AR pathway inhibition. Nucleic Acids Res. 2021;doi: 10.1093/nar/gkab1247.
Somasekharan, S. P., Saxena, N., Zhang, F., Beraldi, E., Huang, J. N., Gentle, C., Fazli, L., Thi, M., Sorensen, P. H., & Gleave, M. (2021). Regulation of AR mRNA translation in response to acute AR pathway inhibition. Nucleic acids research, . https://doi.org/10.1093/nar/gkab1247
Somasekharan, Syam Prakash, et al. "Regulation of AR mRNA translation in response to acute AR pathway inhibition." Nucleic acids research vol. (2021). doi: https://doi.org/10.1093/nar/gkab1247
Somasekharan SP, Saxena N, Zhang F, Beraldi E, Huang JN, Gentle C, Fazli L, Thi M, Sorensen PH, Gleave M. Regulation of AR mRNA translation in response to acute AR pathway inhibition. Nucleic Acids Res. 2021 Dec 23; doi: 10.1093/nar/gkab1247. Epub 2021 Dec 23. PMID: 34939643.
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Nucleic Acids Res. 2021 Dec 23; doi: 10.1093/nar/gkab1247. Epub 2021 Dec 23.

Regulation of AR mRNA translation in response to acute AR pathway inhibition.

Nucleic acids research

Syam Prakash Somasekharan, Neetu Saxena, Fan Zhang, Eliana Beraldi, Jia Ni Huang, Christina Gentle, Ladan Fazli, Marisa Thi, Poul H Sorensen, Martin Gleave

Affiliations

  1. Department of Urologic Sciences, University of British Columbia, Vancouver Prostate Centre, Vancouver, Canada.
  2. British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia, Canada and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 34939643 DOI: 10.1093/nar/gkab1247

Abstract

We report a new mechanism of androgen receptor (AR) mRNA regulation and cytoprotection in response to AR pathway inhibition (ARPI) stress in prostate cancer (PCA). AR mRNA translation is coordinately regulated by RNA binding proteins, YTHDF3 and G3BP1. Under ambient conditions m6A-modified AR mRNA is bound by YTHDF3 and translationally stimulated, while m6A-unmodified AR mRNA is bound by G3BP1 and translationally repressed. When AR-regulated PCA cell lines are subjected to ARPI stress, m6A-modified AR mRNA is recruited from actively translating polysomes (PSs) to RNA-protein stress granules (SGs), leading to reduced AR mRNA translation. After ARPI stress, m6A-modified AR mRNA liquid-liquid phase separated with YTHDF3, while m6A-unmodified AR mRNA phase separated with G3BP1. Accordingly, these AR mRNA messages form two distinct YTHDF3-enriched or G3BP1-enriched clusters in SGs. ARPI-induced SG formation is cell-protective, which when blocked by YTHDF3 or G3BP1 silencing increases PCA cell death in response to ARPI stress. Interestingly, AR mRNA silencing also delays ARPI stress-induced SG formation, highlighting its supportive role in triggering this stress response. Our results define a new mechanism for stress adaptive cell survival after ARPI stress involving SG-regulated translation of AR mRNA, mediated by m6A RNA modification and their respective regulatory proteins.

© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

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