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; Wei Zhuo

doi:10.1038/s41467-022-28913-5

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

Nat Commun. 2022 Mar 10;13(1):1248. doi: 10.1038/s41467-022-28913-5.

Authors

Shujie Chen^#^{1

2

3

4}, Lu Zhang^#^{1

3

4}, Mengjie Li^#^{1

3

4}, Ying Zhang^#^{1

2

3

4}, Meng Sun^{1

3

4}, Lingfang Wang⁵, Jiebo Lin⁵, Yun Cui^{1

3

4}, Qian Chen^{1

3

4}, Chenqi Jin^{1

3

4}, Xiang Li^{1

3

4}, Boya Wang^{3

6}, Hao Chen⁷, Tianhua Zhou^{8

9

10}, Liangjing Wang^{11

12

13}, Chih-Hung Hsu¹⁴, Wei Zhuo^{15

16

17}

Affiliations

¹ Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
⁴ Cancer Center, Zhejiang University, Hangzhou, China.
⁵ Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Zhejiang, China.
⁶ Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁷ School of Medicine, Southern University of Science and Technology, Shenzhen, China.
⁸ Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. tzhou@zju.edu.cn.
⁹ Institute of Gastroenterology, Zhejiang University, Hangzhou, China. tzhou@zju.edu.cn.
¹⁰ Cancer Center, Zhejiang University, Hangzhou, China. tzhou@zju.edu.cn.
¹¹ Institute of Gastroenterology, Zhejiang University, Hangzhou, China. wangljzju@zju.edu.cn.
¹² Cancer Center, Zhejiang University, Hangzhou, China. wangljzju@zju.edu.cn.
¹³ Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. wangljzju@zju.edu.cn.
¹⁴ Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Zhejiang, China. ch_hsu@zju.edu.cn.
¹⁵ Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. wzhuo@zju.edu.cn.
¹⁶ Institute of Gastroenterology, Zhejiang University, Hangzhou, China. wzhuo@zju.edu.cn.
¹⁷ Cancer Center, Zhejiang University, Hangzhou, China. wzhuo@zju.edu.cn.

^# Contributed equally.

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.

MeSH terms

Animals
Colorectal Neoplasms* / pathology
Fusobacterium nucleatum*
Gastrointestinal Microbiome*
Humans
Methyltransferases* / genetics
Methyltransferases* / metabolism
Neoplasm Metastasis
Signal Transduction

Substances

Methyltransferases
METTL3 protein, human