Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis

Shujie Chen,, Lu Zhang, Mengjie Li, Ying Zhang, Meng Sun, Lingfang Wang, Jiebo Lin, Yun Cui, Qian Chen, Chenqi Jin, Xiang Li, Boya Wang, Hao Chen, Tianhua Zhou (), Liangjing Wang (), Chih-Hung Hsu () and Wei Zhuo ()
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Shujie Chen,: Zhejiang University School of Medicine
Lu Zhang: Zhejiang University School of Medicine
Mengjie Li: Zhejiang University School of Medicine
Ying Zhang: Zhejiang University School of Medicine
Meng Sun: Zhejiang University School of Medicine
Lingfang Wang: Zhejiang University School of Medicine
Jiebo Lin: Zhejiang University School of Medicine
Yun Cui: Zhejiang University School of Medicine
Qian Chen: Zhejiang University School of Medicine
Chenqi Jin: Zhejiang University School of Medicine
Xiang Li: Zhejiang University School of Medicine
Boya Wang: Zhejiang University
Hao Chen: Southern University of Science and Technology
Tianhua Zhou: Zhejiang University School of Medicine
Liangjing Wang: Zhejiang University
Chih-Hung Hsu: Zhejiang University School of Medicine
Wei Zhuo: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, however, the underlying mechanisms remain elusive. Here, we uncover that Fusobacterium nucleatum (F. nucleatum) induces a dramatic decline of m6A modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulation of an m6A methyltransferase METTL3, contributing to inducation of CRC aggressiveness. Mechanistically, we characterized forkhead box D3 (FOXD3) as a transcription factor for METTL3. F. nucleatum activates YAP signaling, inhibits FOXD3 expression, and subsequently reduces METTL3 transcription. Downregulation of METTL3 promotes its target kinesin family member 26B (KIF26B) expression by reducing its m6A levels and diminishing YTHDF2-dependent mRNA degradation, which contributes to F. nucleatum-induced CRC metastasis. Moreover, METTL3 expression is negatively correlated with F. nucleatum and KIF26B levels in CRC tissues. A high expression of KIF26B is also significantly correlated with a shorter survival time of CRC patients. Together, our findings provide insights into modulating human m6A epitranscriptome by gut microbiota, and its significance in CRC progression.

Date: 2022
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DOI: 10.1038/s41467-022-28913-5

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