CACUL1 and osteosarcoma: MLN4924 is an inhibitor of NEDD8-activating enzyme (NAE), which in osteosarcoma reduces the ubiquitination and stabilizes the expression of the cullin substrate retinoid orphan nuclear receptor alpha (RORα), thereby antagonizing BMAL1 activation, inducing growth inhibition, and G2/M cell cycle arrest in U2OS cells [123].