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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Cotter, KA; Gallon, J; Uebersax, N; Rubin, P; Meyer, KD; Piscuoglio, S; Jaffrey, SR; Rubin, MA

Published Date

  • August 2021

Published In

Volume / Issue

  • 19 / 8

Start / End Page

  • 1398 - 1411

PubMed ID

  • 34088870

Pubmed Central ID

  • PMC8349875

Electronic International Standard Serial Number (EISSN)

  • 1557-3125

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-21-0014

Language

  • eng

Conference Location

  • United States