Post-transcriptional modification of m 6 A methylase METTL3 regulates ERK-induced androgen-deprived treatment resistance prostate cancer.

As the most common modification of RNA, N 6 -methyladenosin (m 6 A) has been confirmed to be involved in the occurrence and development of various cancers. However, the relationship between m 6 A and castration resistance prostate cancer (CRPC), has not been fully studied. By m 6 A-sequencing of patient cancer tissues, we identified that the overall level of m 6 A in CRPC was up-regulated than castration sensitive prostate cancer (CSPC). Based on the analysis of m 6 A-sequencing data, we found m 6 A modification level of HRas proto-oncogene, GTPase (HRAS) and mitogen-activated protein kinase kinase 2 (MEK2 or MAP2K2) were enhanced in CRPC. Specifically, tissue microarray analysis and molecular biology experiments confirmed that METTL3, an m 6 A "writer" up-regulated after castration, activated the ERK pathway to contribute to malignant phenotype including ADT resistance, cell proliferation and invasion. We revealed that METTL3-mediated ERK phosphorylation by stabilizing the transcription of HRAS and positively regulating the translation of MEK2. In the Enzalutamide-resistant (Enz-R) C4-2 and LNCap cell line (C4-2 R , LNCap R ) established in the current study, the ERK pathway was confirmed to be regulated by METTL3. We also found that applying antisense oligonucleotides (ASOs) to target the METTL3/ERK axis can restore Enzalutamide resistance in vitro and in vivo. In conclusion, METTL3 activated the ERK pathway and induced the resistance to Enzalutamide by regulating the m 6 A level of critical gene transcription in the ERK pathway.