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Background <p>Prostate cancer patients harboring <i>TP53</i> 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 <i>TP53</i> mutations is totally unknown.</p> Materials and methods <p>Bioinformatic analysis was employed to assess the transcriptome signature between <i>TP53</i><sup><i>WT</i></sup> and <i>TP53</i><sup><i>Mut</i></sup> prostate cancer and the expression of METTL3 complex in <i>TP53</i><sup><i>WT</i></sup>and <i>TP53</i><sup><i>Mut</i></sup>prostate cancer. Colony formation and growth curve analyses were employed to assess the role of METTL3 in <i>TP53</i><sup><i>Mut</i></sup> prostate cancer. Furthermore, the bioinformatic analyses were utilized for uncovering the underlying mechanism of how METTL3 maintained the malignancy phenotype of <i>TP53</i><sup><i>Mut</i></sup> prostate cancer.</p> Results <p><i>TP53</i> as one of the most frequently mutated genes in prostate cancer. Transcriptome analysis revealed that <i>TP53</i> 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 <i>TP53</i><sup><i>WT</i></sup> prostate tissues. Notably, pharmaceutically blockade of METTL3 drastically inhibited <i>TP53</i> mutated prostate cancer cells growth. Bioinformatic analysis suggested that METTL3 inhibition maintained <i>TP53</i> mutated prostate cancer malignancies via activating MAPK signaling.</p> Conclusions <p>METTL3 serves as a novel targetable vulnerability for prostate cancer. Targeting METTL3 prohibits the <i>TP53</i> mutated prostate cancer growth by inactivating MAPK signaling.</p>

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METTL3 drives malignant progression in TP53-mutant prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Yong Pu,
  • Dan Ye,
  • Nan Dong,
  • Yan Qin,
  • Xiaowei Qi

摘要

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.