CDK-FBX028-MYC Axis: A Potential Molecular Drug Target

SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis bytargeting key proteins for ubiquitylation. We identified a hitherto uncharacterized F-box protein,FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation ofFBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement ofthe MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYCubiquitylation results in an impairment of MYC-driven transcription, transformation andtumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation arestrong and independent predictors of poor outcome. In conclusion, our data suggest thatSCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cellcycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-drivencancers, including breast cancer.