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

TitleMapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance.
Publication TypeJournal Article
Year of Publication2021
AuthorsCotter KA, Gallon J, Uebersax N, Rubin P, Meyer KD, Piscuoglio S, Jaffrey SR, Rubin MA
JournalMol Cancer Res
Volume19
Issue8
Pagination1398-1411
Date Published2021 Aug
ISSN1557-3125
Abstract

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.

DOI10.1158/1541-7786.MCR-21-0014
Alternate JournalMol Cancer Res
PubMed ID34088870
PubMed Central IDPMC8349875
Grant ListP50 CA211024 / CA / NCI NIH HHS / United States
R01 CA186702 / CA / NCI NIH HHS / United States