Mapping of m6A and its regulatory targets in prostate cancer reveals a METTL3-Low induction of therapy resistance

Abstract

Recent evidence has highlighted the role of N6-methyladeMETTL3 knockdown. We also examined the relationship nosine (m6A) in the regulation of mRNA expression, stability, between METTL3 and androgen signaling and discovered the and translation, supporting a potential role for posttranscripupregulation of a hepatocyte nuclear factor–driven gene signational regulation mediated by m6A in cancer. Here, we explore ture that is associated with therapy resistance in prostate cancer. prostate cancer as an exemplar and demonstrate that low levels Significantly, METTL3 knockdown rendered the cells resistant of N6-adenosine-methyltransferase (METTL3) is associated with to androgen receptor antagonists via an androgen receptor–advanced metastatic disease. To investigate this relationship, we independent mechanism driven by the upregulation of nuclear generated the first prostate m6A maps, and further examined receptor NR5A2/LRH-1. how METTL3 regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding Implications: These findings implicate changes in m6A as a mechextracellular matrix proteins are consistently upregulated with anism for therapy resistance in metastatic prostate cancer.