METTL3 drives malignant progression in TP53-mutant prostate cancer.

BACKGROUND: Prostate cancer patients harboring TP53 mutations exhibit a more aggressive and chemo-resistant phenotype. Unfortunately, attempts to identify the vulnerabilities that could be exploited to overcome these aggressive malignancies have made only minimal progress in recent years. Consequently, there is an immediate requirement to investigate novel therapeutic strategies for this subclass. METTL3 complex, knowing to govern m6A dynamic alteration, has been suggested to be a critical therapeutic target across human cancer. However, the role of METTL3 in prostate cancer harboring TP53 mutations is totally unknown. MATERIALS AND METHODS: Bioinformatic analysis was employed to assess the transcriptome signature between TP53(WT) and TP53(Mut) prostate cancer and the expression of METTL3 complex in TP53(WT)and TP53(Mut)prostate cancer. Colony formation and growth curve analyses were employed to assess the role of METTL3 in TP53(Mut) prostate cancer. Furthermore, the bioinformatic analyses were utilized for uncovering the underlying mechanism of how METTL3 maintained the malignancy phenotype of TP53(Mut) prostate cancer. RESULTS: TP53 as one of the most frequently mutated genes in prostate cancer. Transcriptome analysis revealed that TP53 mutation significantly downregulated genes associated with prohibiting proliferation. Moreover, the core catalytic subunit, METTL3, was found to be aberrantly upregulated in TP53 mutated prostate cancer compared to that in normal and TP53(WT) prostate tissues. Notably, pharmaceutically blockade of METTL3 drastically inhibited TP53 mutated prostate cancer cells growth. Bioinformatic analysis suggested that METTL3 inhibition maintained TP53 mutated prostate cancer malignancies via activating MAPK signaling. CONCLUSIONS: METTL3 serves as a novel targetable vulnerability for prostate cancer. Targeting METTL3 prohibits the TP53 mutated prostate cancer growth by inactivating MAPK signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11033-025-11160-4.