Regular exercise suppresses steatosis‐associated liver cancer development by degrading E2F1 and c‐Myc via circadian gene upregulation

Abstract Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis‐associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non‐exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c‐Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c‐Myc was transcriptionally unchanged but degraded at the post‐translational level by exercise. Cry2, which is regulated by the Skp1‐Cul1‐FBXL3 (SCF FBXL3 ) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c‐Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development.