Introduction: Melanoma is a malignant tumor that seriously affects patients. The pathogenesis of malignant melanoma is complex, and the cell cycle is closely related to tumor progression. Based on the catalog of cancer somatic mutations, we found that overexpression of the E2F3  gene ranked first in percentage increase in not only melanoma but also in all human cancer tissues. However, there are few studies on the high expression of E2F3  and its carcinogenic mechanism in melanoma. 
Methods and results: We found that E2F3  showed extensive copy number amplification that was positively correlated with the expression level. Patients with high copy number had a significantly poorer prognosis. We also found that E2F3  levels were significantly negatively correlated with promoter methylation. However, we showed that the E2F3  promoter region is hypomethylated, and in normal cells or tumor cells, the methylation level did not correlate with expression. Finally, we knocked down the E2F3  gene in melanoma cells by shRNA. Colony formation, anchorage-dependent growth, and EdU cell proliferation experiments showed a significant decrease in proliferation. Flow cytometry showed a significant increase in the G0/G1 ratio. 
Conclusion: It can be speculated that copy number amplification and other mechanisms result in the high expression of E2F3  in melanoma, which promotes tumor progression by involving the cell cycle. E2F3  is a good target for the treatment of melanoma.
Keywords: E2F3 , melanoma, mechanism, overexpression, copy number, methylation