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Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.

Publication ,  Journal Article
Cotter, KA; Gallon, J; Uebersax, N; Rubin, P; Meyer, KD; Piscuoglio, S; Jaffrey, SR; Rubin, MA
Published in: Mol Cancer Res
August 2021

Recent evidence has highlighted the role of N 6-methyladenosine (m6A) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by m6A in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of N 6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate m6A maps, and further examined how METTL3 regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding extracellular matrix proteins are consistently upregulated with METTL3 knockdown. We also examined the relationship between METTL3 and androgen signaling and discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knockdown rendered the cells resistant to androgen receptor antagonists via an androgen receptor-independent mechanism driven by the upregulation of nuclear receptor NR5A2/LRH-1. IMPLICATIONS: These findings implicate changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.

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Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

August 2021

Volume

19

Issue

8

Start / End Page

1398 / 1411

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Prostate
  • Oncology & Carcinogenesis
  • Methyltransferases
  • Male
  • Humans
 

Citation

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Cotter, K. A., Gallon, J., Uebersax, N., Rubin, P., Meyer, K. D., Piscuoglio, S., … Rubin, M. A. (2021). Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance. Mol Cancer Res, 19(8), 1398–1411. https://doi.org/10.1158/1541-7786.MCR-21-0014
Cotter, Kellie A., John Gallon, Nadine Uebersax, Philip Rubin, Kate D. Meyer, Salvatore Piscuoglio, Samie R. Jaffrey, and Mark A. Rubin. “Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.Mol Cancer Res 19, no. 8 (August 2021): 1398–1411. https://doi.org/10.1158/1541-7786.MCR-21-0014.
Cotter KA, Gallon J, Uebersax N, Rubin P, Meyer KD, Piscuoglio S, et al. Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance. Mol Cancer Res. 2021 Aug;19(8):1398–411.
Cotter, Kellie A., et al. “Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.Mol Cancer Res, vol. 19, no. 8, Aug. 2021, pp. 1398–411. Pubmed, doi:10.1158/1541-7786.MCR-21-0014.
Cotter KA, Gallon J, Uebersax N, Rubin P, Meyer KD, Piscuoglio S, Jaffrey SR, Rubin MA. Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance. Mol Cancer Res. 2021 Aug;19(8):1398–1411.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

August 2021

Volume

19

Issue

8

Start / End Page

1398 / 1411

Location

United States

Related Subject Headings

  • Up-Regulation
  • Signal Transduction
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Androgen
  • Prostatic Neoplasms
  • Prostate
  • Oncology & Carcinogenesis
  • Methyltransferases
  • Male
  • Humans