Colorectal cancer is one of the commonmalignant tumors, which seriously endangers the health of the nation. Despitethe development of treatment methods for colorectal cancer, the survival ofpatients with advanced metastatic colorectal cancer are still unsatisfactory.Also, with continuing progress of research methods such as metagenomicsequencing, it has been found that gut microbiota can widely affect thephysiological and pathological functions of host cells, and a variety ofmicroenvironmental bacteria participate in the occurrence and development ofcolorectal cancer. However, an important question remains unanswered. How doesthe disorder of the microbiota systematically affect the progression andmetastasis of host colorectal cancer cells?
Recently, the research group of Prof. ZHUOWei and Prof. ZHOU Tianhua from the Zhejiang University School of BasicMedicine published a research paper titled “Fusobacterium nucleatum reducesMETTL3-mediated m6A modification and contributes to colorectal cancermetastasis” in Nature Communications. For the first time, it is revealed thatthe disturbance of special human intestinal flora may alter the epitranscriptomemodification of human host intestinal cancer epithelial cells, therebysystematically affecting the gene expression of colorectal cancer cells andpromoting the malignancy and metastasis of colorectal cancer cells.
The research group has long been dedicatedto the research on the mechanism of gastrointestinal tumor metastasis.Previously, Prof. ZHUO Wei cooperated with the research group of CHEN Shujiefrom the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine,provided the evidence that the gut microbiota, Fusobacterium nucleatum, isdirectly involved in the metastasis of colorectal cancer cells for the firsttime. The results were published in Gut Microbes in 2020.
Whereafter, Prof. ZHUO Wei's team foundthat Fusobacterium nucleatum can significantly reduce the m6A modificationlevel of the overall mRNA in colorectal cancer cells and tumor tissues fromcolorectal cancer patients. The significant reduction in m6A modification levelmay be due to the inhibition of the main m6A methyltransferase METTL3 byFusobacterium nucleatum. By introducing the METTL3 m6A enzyme activity mutantplasmid, the research group further confirmed that Fusobacterium nucleatumwhich promotes metastasis of colorectal cancer cells is partially dependent onm6A modification. Regarding how Fusobacterium nucleatum regulates METTL3expression, the research group identified FOXD3 as the first transcriptionfactor for METTL3. They found that Fusobacterium nucleatum enriched in themicroenvironment can inhibit the Hippo pathway and activate the Yap signalingpathway. This is also the first report that microenvironmental flora canregulate the Hippo-Yap pathway of host colorectal cancer cells. Activation ofYap affects the transcriptional promotion of METTL3 by FOXD3, ultimatelyresulting in a systemic reduction in overall mRNA m6A modification levels incolorectal cancer cells.
The research group used m6A-Seq and RNA-Seqanalysis to identify KIF26B as one of the important target genes regulated byMETTL3. Fusobacterium nucleatum treatment decreased m6A modification levels ofKIF26B, directly reducing its mRNA degradation mediated by the m6A readerYTHDF2, thereby stabilizing the expression level of KIF26B. Through a varietyof in vitro and in vivo models, the research group found that KIF26B is crucialfor maintaining the migration and metastasis ability of colorectal cells. Theloss of KIF26B can significantly inhibit the migration and metastasis abilityof colorectal cancer cells. The gut microenvironment with abundantFusobacterium nucleatum can maintain the expression level of KIF26B inmetastatic colorectal cancer cells by affecting its m6A modification, therebypromoting metastasis of colorectal cancer cells.
This study explains for the first time thatthe disturbance of the special microbiota in intestinal microenvironment maysystematically 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 newtumor-microbiota interaction mediated by the YAP/FOXD3/METTL3/KIF26B pathwaythat plays an important role in promoting the metastasis of colorectal cancercells.
