Background: Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) are essential for tumor cells metastasis. However, the effect of epigeneticmodifications on this transition is unclear. Objective: We aimed to explore the key histone modifications and hub genes of EMT/MET during ColorectalCancer (CRC) metastasis. Methods: The differentially expressed genes and differentially histone modified genes were identified.Based on the histone modification features, the up- and down-regulated genes were predicted by RandomForest algorithm. Through protein-protein interaction network and Cytoscape analysis, the hubgenes with histone modification changes were selected. GO, KEGG and survival analyses were performedto confirm the importance of the hub genes. Results: It was found that H3K79me3 plays an important role in EMT/MET. And the 200-300bp and400-500bp downstream of TSS may be the key regulatory regions of H3K79me3. Moreover, we foundthat the expression of the hub genes was down-regulated in EMT and then up-regulated in MET. Andthe changes of the hub genes expression were consistent with the changes of H3K79me3 signal in thespecific regions of the genome. Finally, the hub genes KRT8 and KRT18 were involved in the metastasisprocess and were significantly related to the survival time. Conclusion: H3K79me3 may be crucial for EMT/MET, and the hub genes KRT8 and KRT18 may bethe key genes in this process.