Colorectal cancer is one of the common malignant tumors, which seriously endangers the health of the nation. Despite the development of treatment methods for colorectal cancer, the survival of patients with advanced metastatic colorectal cancer are still unsatisfactory. Also, with continuing progress of research methods such as metagenomic sequencing, it has been found that gut microbiota can widely affect the physiological and pathological functions of host cells, and a variety of microenvironmental bacteria participate in the occurrence and development of colorectal cancer. However, an important question remains unanswered. How does the disorder of the microbiota systematically affect the progression and metastasis of host colorectal cancer cells?

Recently, the research group of Prof. ZHUO Wei and Prof. ZHOU Tianhua from the Zhejiang University School of Basic Medicine published a research paper titled “Fusobacterium nucleatum reduces METTL3-mediated m⁶A modification and contributes to colorectal cancer metastasis” in Nature Communications. For the first time, it is revealed that the disturbance of special human intestinal flora may alter the epitranscriptome modification of human host intestinal cancer epithelial cells, thereby systematically affecting the gene expression of colorectal cancer cells and promoting the malignancy and metastasis of colorectal cancer cells.

The research group has long been dedicated to the research on the mechanism of gastrointestinal tumor metastasis. Previously, Prof. ZHUO Wei cooperated with the research group of CHEN Shujie from the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, provided the evidence that the gut microbiota, Fusobacterium nucleatum, is directly involved in the metastasis of colorectal cancer cells for the first time. The results were published in Gut Microbes in 2020.

Whereafter, Prof. ZHUO Wei's team found that Fusobacterium nucleatum can significantly reduce the m⁶A modification level of the overall mRNA in colorectal cancer cells and tumor tissues from colorectal cancer patients. The significant reduction in m⁶A modification level may be due to the inhibition of the main m⁶A methyltransferase METTL3 by Fusobacterium nucleatum. By introducing the METTL3 m⁶A enzyme activity mutant plasmid, the research group further confirmed that Fusobacterium nucleatum which promotes metastasis of colorectal cancer cells is partially dependent on m6A modification. Regarding how Fusobacterium nucleatum regulates METTL3 expression, the research group identified FOXD3 as the first transcription factor for METTL3. They found that Fusobacterium nucleatum enriched in the microenvironment can inhibit the Hippo pathway and activate the Yap signaling pathway. This is also the first report that microenvironmental flora can regulate the Hippo-Yap pathway of host colorectal cancer cells. Activation of Yap affects the transcriptional promotion of METTL3 by FOXD3, ultimately resulting in a systemic reduction in overall mRNA m⁶A modification levels in colorectal cancer cells.

The research group used m⁶A-Seq and RNA-Seq analysis to identify KIF26B as one of the important target genes regulated by METTL3. Fusobacterium nucleatum treatment decreased m6A modification levels of KIF26B, directly reducing its mRNA degradation mediated by the m⁶A reader YTHDF2, thereby stabilizing the expression level of KIF26B. Through a variety of in vitro and in vivo models, the research group found that KIF26B is crucial for maintaining the migration and metastasis ability of colorectal cells. The loss of KIF26B can significantly inhibit the migration and metastasis ability of colorectal cancer cells. The gut microenvironment with abundant Fusobacterium nucleatum can maintain the expression level of KIF26B in metastatic colorectal cancer cells by affecting its m⁶A modification, thereby promoting metastasis of colorectal cancer cells.

This study explains for the first time that the disturbance of the special microbiota in intestinal microenvironment may systematically modulate the epitranscriptome modification of the host, resulting in abnormal regulation of gene expression in colorectal cancer cells, and promoting colorectal cancer metastasis. This work reveals a new tumor-microbiota interaction mediated by the YAP/FOXD3/METTL3/KIF26B pathway that plays an important role in promoting the metastasis of colorectal cancer cells.

Source: the research group of Prof. ZHUO Wei and Prof. ZHOU Tianhua