PRJNA793361
Homo sapiens Raw sequence reads
Dysregulated cholesterol metabolism is a hallmark of colorectal cancer cells. However, the usage of cholesterol-lowering agents seemed to have no benefit in CRC patients. In this study, we focused on the cholesterol- nuclear receptors axis as a strategy. Cholesterol and its derivatives work as ligands for different nuclear receptors, thus promoting cancer progression. The key NR downstream of cholesterol in CRC is unknown. Here, we treated CRC cells with atorvastatin, a cholesterol-lowering agent, and conditioned medium supplemented with lipoprotein-depleted fetal bovine serum, and then detected the change of the putative NRs. The results revealed that ROR levels exhibited the most obvious increases in CRC cells subjected them to cholesterol deprivation. ROR agonists significantly inhibited CRC cells proliferation and migration in vitro and in vivo. Also, ROR overexpression repressed CRC cells proliferation and migration in vitro and in vivo and ROR knockdown promoted it. Mechanistically, ROR agonists promoted c-myc degradation by activating the transcription of the ubiquitinase NEDD4. Intriguingly, the combination of ROR agonists and atorvastatin had a synergistic effect on inhibiting CRC cells. These findings demonstrate that the cholesterol- ROR axis is is important for maintaining c-myc protein levels. Combination therapy with atorvastatin and ROR agonist is a promising therapeutic strategy for CRC