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

Recent evidence has highlighted the role of -methyladenosine (mA) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by mA in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of -adenosine-methyltransferase () is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate mA 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 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 . IMPLICATIONS: These findings implicate changes in mA as a mechanism for therapy resistance in metastatic prostate cancer.