Our findings demonstrated that SMYD2 could epigenetically enhance the protein stability of EZH2 via methylation modification at the K307 position to repress TET1 through H3K27me3 modification at TET1 promoter region, resulting in a further decrease in tumor suppressor gene p53 expression and contributed to the tumorigenesis of GIST. The gene discussed is TP53; the disease is gastrointestinal stromal tumor.