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Exploring the epigenetic regulation mechanism of colorectal cancer (CRC) from the perspective of N6-methyladenosine (m6A) modification may provide a new target for tumor therapy. Analysis using high-throughput RNA-seq profile from TCGA found that the gene expression of Methyltransferase-like 3 (METTL3) was significantly upregulated among 20 m6A binding proteins in CRC, which was also validated in CRC cancer tissues and cell lines. Moreover, transcriptome sequencing in METTL3 knockdown cells using CRISPR/Cas9 editing suggested that EphA2 and VEGFA were differential expression, which were enriched in the vasculature development, PI3K/AKT and ERK1/2 signal pathway through the functional enrichment analysis. The results in vitro revealed that METTL3 as the m6A “writers” participates the methylation of EphA2 and VEGFA, which were recognized by the m6A “readers”, insulin-like growth factor 2 mRNA binding protein 2/3 (IGF2BP2/3), to prevent their mRNA degradation. In addition, EphA2 and VEGFA targeted by METTL3 via different IGF2BP-dependent mechanisms were found to promote vasculogenic mimicry (VM) formation via PI3K/AKT/mTOR and ERK1/2 signaling in CRC. The study suggests that intervention with m6A-binding proteins (METTL3 and IGF2BP2/3) may provide a potential diagnostic or prognostic target of VM-based anti-metastasis drugs for CRC.

N6-methyladenosine (m 6 A) modification is an important regulatory factor affecting diseases, including multiple cancers and it is a developing direction for targeted disease therapy. Here, we present the M6ADD (m 6 A-diseases database) database, a public data resource containing manually curated data on potential m 6 A-disease associations for which some experimental evidence is available; the related highthroughput sequencing data are also provided and analysed by using different computational methods. To give researchers a tool to query the m6A modification data, the M6ADD was designed as a webbased comprehensive resource focusing on the collection, storage and online analysis of m6A modifications, aimed at exploring the associations between m6A modification and gene disorders and diseases. The M6ADD includes 222 experimentally confirmed m 6 A-disease associations, involving 59 diseases from a review of more than 2000 published papers. The M6ADD also includes 409,229 m 6 A-disease associations obtained by computational and statistical methods from 30 high-throughput sequencing datasets. In addition, we provide data on 5239 potential m 6 A regulatory proteins related to 24 cancers based on network analysis prediction methods. In addition, we have developed a tool to explore the function of m 6 A-modified genes through the protein-protein interaction networks. The M6ADD can be accessed at http://m6add.edbc.org/.

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