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具核梭杆菌降低 METTL3 介导的 mA 修饰并促进结直肠癌转移。

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

机构信息

Department of Cell Biology and Department of Gastroenterology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

出版信息

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

DOI:10.1038/s41467-022-28913-5
PMID:35273176
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8913623/
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 mA modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulation of an mA 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 mA 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 mA epitranscriptome by gut microbiota, and its significance in CRC progression.

摘要

微生物群-宿主相互作用在结直肠癌 (CRC) 的进展中起着关键作用，但潜在的机制仍难以捉摸。在这里，我们发现具核梭杆菌 (F. nucleatum) 通过下调 mA 甲基转移酶 METTL3，导致 CRC 细胞和患者来源的异种移植物 (PDX) 组织中 mA 修饰的急剧下降，从而促进 CRC 的侵袭性。在机制上，我们将叉头框 D3 (FOXD3) 鉴定为 METTL3 的转录因子。F. nucleatum 激活 YAP 信号通路，抑制 FOXD3 表达，进而降低 METTL3 转录。METTL3 的下调通过降低其 mA 水平和减少 YTHDF2 依赖的 mRNA 降解来促进其靶基因驱动蛋白家族成员 26B (KIF26B) 的表达，这有助于 F. nucleatum 诱导的 CRC 转移。此外，CRC 组织中 METTL3 的表达与 F. nucleatum 和 KIF26B 的水平呈负相关。KIF26B 的高表达也与 CRC 患者的生存时间较短显著相关。总之，我们的研究结果提供了对肠道微生物群调节人类 mA 转录组及其在 CRC 进展中的意义的深入了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/95c34a671e42/41467_2022_28913_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/092ebbaeb3b5/41467_2022_28913_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/3a3eeeb0a79d/41467_2022_28913_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/e83b387852f4/41467_2022_28913_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/95c34a671e42/41467_2022_28913_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/7d995c947495/41467_2022_28913_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/2f14f0afc1c8/41467_2022_28913_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/2f3c6a33d6ce/41467_2022_28913_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/092ebbaeb3b5/41467_2022_28913_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/3a3eeeb0a79d/41467_2022_28913_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/e83b387852f4/41467_2022_28913_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2519/8913623/95c34a671e42/41467_2022_28913_Fig7_HTML.jpg

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