Post-transcriptional modification of m6A methylase METTL3 regulates ERK-induced androgen-deprived treatment resistance prostate cancer

As the most common modification of RNA, N6-methyladenosin (m(6)A) has been confirmed to be involved in the occurrence and development of various cancers. However, the relationship between m6A 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 upregulated 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 (C4-2R, LNCapR) 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 m6A level of critical gene transcription in the ERK pathway.

Automated summary

Through m(6)A-sequencing of patient cancer tissues, we found that the overall level of m(6)A was upregulated in castration resistance prostate cancer (CRPC) compared to castration sensitive prostate cancer (CSPC). Further analysis revealed enhanced m(6)A modification of HRAS and MEK2 in CRPC. METTL3 was found to activate the ERK pathway to promote ADT resistance, cell proliferation, and invasion. Targeting the METTL3/ERK axis can restore Enzalutamide resistance in vitro and in vivo.