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

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.

The Role of The Tumor Microbiome in Tumor Development and Its Treatment

“…F. nucleatum abundance correlates with high glucose metabolism in CRC patients, and F. nucleatum targetes lncRNA ENO1-IT1 promotes CRC glycolysis and tumor progression (94). F. nucleatum induced a dramatic decrease in m 6 A modification in CRC cells and patient-derived xenograft tissues through downregulation of the m 6 A methyltransferase METTL3, resulting in CRC aggressiveness (95). A study quantified F. nucleatum DNA in 181 colorectal cancer liver metastasis (CRLM) specimens and found that F. nucleatumpositive CRLM showed a significantly lower density of CD8 + T cells and a higher density of MDSCs compared to F. nucleatumnegative CRLM, and the difference was statistically significant, but the relationship between F. nucleatum and density of tumorassociated macrophages (TAMs) was not statistically significant (96).…”

The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration

“…A study also finds that FadA promotes SW480 cell growth and proliferation in a dose and time-dependent manner [ 19 ]. In addition, Fn-induced miR-4717 promotes CRC cell line proliferation via METTL3-dependent m6A modification [ 20 , 21 , 22 ]. Lee et al [ 23 ] suggested that Fn might be linked to promoting CRC cell growth, invasion, and pro-tumoral immune responses in MSI-high CRCs.…”

“…FOXD3 is a transcription factor for METTL3, an m6A methyltransferase, and there is evidence that Fn could diminish the expression of FOXD3 and suppress the transcription of METTL3 via YAP pathway activation. Its target, KIF26B, is promoted by the decline in m6A modifications and mRNA degradation, which are responsible for Fn-related CRC metastasis [ 22 ].…”

YTHDF2-mediated Distinct m6A Regulations Bifurcate Ferroptosis and Apoptosis in BHPF-induced Developmental Defects

“…RNA modification is one of the common mechanisms by which environmental stimuli influence cellular functions 4,[19][20][21][22] . We found that BHPF induced tissue-specific ferroptosis and apoptosis in an m 6 A dependent manner, leading to cardiac and vascular developmental defects, respectively.…”