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Background <p>Colorectal cancer (CRC), a prevalent malignancy of the digestive system, is often characterized by poor patient prognosis due to high rates of recurrence and metastasis. N6-methyladenosine (m<sup>6</sup>A) modification represents a crucial epigenetic mechanism regulating RNA (including lncRNAs) function and is increasingly implicated in tumor progression. However, the underlying regulatory mechanism of m<sup>6</sup>A modification in CRC pathogenesis remain incompletely understood.</p> Methods <p>We first integrated bioinformatic analysis data, which revealed a significant positive correlation and co-enrichment of methyltransferase-Like 3 (METTL3) and the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in a high-risk prognostic signature. Functional validation included in vitro assessments of cellular proliferation, migration, invasion, apoptosis, and m<sup>6</sup>A methylation levels following METTL3 or MALAT1 suppression, alongside in vivo xenograft tumor models to evaluate the effects of a METTL3 inhibitor on tumor growth dynamics and m<sup>6</sup>A modification levels. Finally, mechanistic profiling was conducted to dissect NF-κB pathway activity.</p> Results <p>METTL3 and MALAT1 were markedly upregulated in CRC tissues and cell lines. Molecular docking identified trihydroxy methylcyclohexane aminoglycoside (TMA) as a high-affinity METTL3-binding compound. Inhibition of METTL3 or MALAT1 significantly impaired cellular proliferation, migration, and invasion, while promoting apoptosis. RNA immunoprecipitation quantitative PCR (RIP-qPCR) and RNA stability assays established that METTL3 maintains MALAT1 stability <i>via</i> m<sup>6</sup>A modification. In vivo, suppression of METTL3 potently inhibited xenograft tumor growth without observable toxicity. Western blot and immunohistochemistry (IHC) analyses further verified that this METTL3-MALAT1 axis activates the NF-κB pathway by modulating IκBα degradation and p65 nuclear translocation.</p> Conclusions <p>Collectively, our work elucidates the METTL3-m<sup>6</sup>A-MALAT1-NF-κB regulatory axis in CRC, advancing the understanding of epigenetic mechanisms in cancer progression and providing a theoretical foundation for developing METTL3-targeted therapeutic strategies.</p>

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METTL3-mediated m6A modification of lncRNA MALAT1 promotes colorectal cancer progression by activating the NF-κB signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月25日

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  • Shuangming Lin,
  • Hao Zeng,
  • Xueyi Xue,
  • Baodong Liao,
  • Hao Lin,
  • Yuhui Wang,
  • Dongbo Xu

摘要

Background

Colorectal cancer (CRC), a prevalent malignancy of the digestive system, is often characterized by poor patient prognosis due to high rates of recurrence and metastasis. N6-methyladenosine (m6A) modification represents a crucial epigenetic mechanism regulating RNA (including lncRNAs) function and is increasingly implicated in tumor progression. However, the underlying regulatory mechanism of m6A modification in CRC pathogenesis remain incompletely understood.

Methods

We first integrated bioinformatic analysis data, which revealed a significant positive correlation and co-enrichment of methyltransferase-Like 3 (METTL3) and the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in a high-risk prognostic signature. Functional validation included in vitro assessments of cellular proliferation, migration, invasion, apoptosis, and m6A methylation levels following METTL3 or MALAT1 suppression, alongside in vivo xenograft tumor models to evaluate the effects of a METTL3 inhibitor on tumor growth dynamics and m6A modification levels. Finally, mechanistic profiling was conducted to dissect NF-κB pathway activity.

Results

METTL3 and MALAT1 were markedly upregulated in CRC tissues and cell lines. Molecular docking identified trihydroxy methylcyclohexane aminoglycoside (TMA) as a high-affinity METTL3-binding compound. Inhibition of METTL3 or MALAT1 significantly impaired cellular proliferation, migration, and invasion, while promoting apoptosis. RNA immunoprecipitation quantitative PCR (RIP-qPCR) and RNA stability assays established that METTL3 maintains MALAT1 stability via m6A modification. In vivo, suppression of METTL3 potently inhibited xenograft tumor growth without observable toxicity. Western blot and immunohistochemistry (IHC) analyses further verified that this METTL3-MALAT1 axis activates the NF-κB pathway by modulating IκBα degradation and p65 nuclear translocation.

Conclusions

Collectively, our work elucidates the METTL3-m6A-MALAT1-NF-κB regulatory axis in CRC, advancing the understanding of epigenetic mechanisms in cancer progression and providing a theoretical foundation for developing METTL3-targeted therapeutic strategies.