METTL3 drives malignant progression in TP53-mutant prostate cancer

  • Mol Biol Rep. 2025 Nov 11;53(1):66. doi: 10.1007/s11033-025-11160-4.
Yong Pu  1 ,  Dan Ye  2 ,  Nan Dong  2 ,  Yan Qin  3 ,  Xiaowei Qi  4
Affiliations
  • 1. Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China.
  • 2. Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, China.
  • 3. Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China. [email protected].
  • 4. Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China. [email protected].
PMID: 41217561 DOI: 10.1007/s11033-025-11160-4
Abstract

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 TP53WT and TP53Mut prostate Cancer and the expression of METTL3 complex in TP53WTand TP53Mutprostate Cancer. Colony formation and growth curve analyses were employed to assess the role of METTL3 in TP53Mut prostate Cancer. Furthermore, the bioinformatic analyses were utilized for uncovering the underlying mechanism of how METTL3 maintained the malignancy phenotype of TP53Mut 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 TP53WT 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.

Keywords
TP53 mutation; M6A modification; MAPK signaling; METTL3; Prostate cancer.
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