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

Year: 2021
Type: article
Abstract: ABSTRACT Recent evidence has highlighted the role of N 6 -methyladenosine (m 6 A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post-transcriptional regulation mediated by m 6 A 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 explore this relationship, we generated the first prostate m 6 A 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, implicating changes in m 6 A as a mechanism for therapy resistance in metastatic prostate cancer.
DOI: 10.1158/1541-7786.mcr-21-0014
Authors: Kellie A. Cotter, John Gallon, Nadine Uebersax, Philip Rubin, Kate D. Meyer, Salvatore Piscuoglio, Samie R. Jaffrey, Mark A. Rubin
Institutions: University of Bern, University of Basel, Duke University, Duke Medical Center, University Hospital of Basel, St. Claraspital, Weill Cornell Medicine, University Hospital of Bern
Language: English
Open Access status: hybrid
Funders: Prostate Cancer Foundation, Universität Basel, University of Bern, National Institutes of Health, Weill Cornell Medical College, National Cancer Institute, National Institute of Neurological Disorders and Stroke
OpenAlex ID: W3165365611
FWCI: 1.931
Cites: 73
Cited by: 34
Related to: 10