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

Shujie Chen,,Lingfang Wang,Mengjie Li,Jiebo Lin,Boya Wang,Meng Sun,Yun Cui,Liangjing Wang,Chih-Hung Hsu,Wei Zhuo,Hao Chen,Ying Zhang,Chenqi Jin,Qian Chen,Lu Zhang,Tianhua Zhou,Xiang Li

doi:10.1038/s41467-022-28913-5

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.

Highlights

Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, the underlying mechanisms remain elusive
F. nucleatum activates yes[1] associated transcriptional regulator (YAP) signaling to inhibit forkhead box D3 (FOXD3), which we identified as a positive transcription factor of methyltransferase-like 3 (METTL3)
F. nucleatum reduces METTL3-mediated m6A modifications in human CRC cells and patient-derived xenograft (PDX) tissues

Summary

Introduction

Microbiota-host interactions play critical roles in colorectal cancer (CRC) progression, the underlying mechanisms remain elusive. 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. 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. Whether microbiota–host interactions influence the m6A modification of host mRNA and its underlying mechanisms remain elusive. We report that F. nucleatum induces a significant decrease in m6A levels in human CRC cells and in patient-derived xenograft (PDX) tissues. F. nucleatum activates yes[1] associated transcriptional regulator (YAP) signaling to inhibit forkhead box D3 (FOXD3), which we identified as a positive transcription factor of methyltransferase-like 3 (METTL3). This work reveals that F. nucleatum reduces m6A modifications to promote CRC aggressiveness through the YAP/FOXD3/METTL3/KIF26B axis

Methods

Results

Conclusion