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

• DOI: 10.1038/s41467-022-28913-5
• Publication Date: 2022-03-10T11:06:06Z
• Authors: 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; Wei Zhuo
• Keywords: 0303 health sciences; Fusobacterium nucleatum; Science; Q; Methyltransferases; Article; Gastrointestinal Microbiome; 3. Good health; 03 medical and health sciences; Animals; Humans; Neoplasm Metastasis; Colorectal Neoplasms; Signal Transduction

AbstractMicrobiota-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.