A chemical inhibitor of the Skp2/p300 interaction that promotes p53-mediated apoptosis

M. Oh, J. H. Lee, H. Moon, Y.-J. Hyun, and H. S. Lim

Skp2 is thought to have two critical roles in tumorigenesis. As part of SCF^Skp2 ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Here we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screening of a combinatorial cyclic peptoid library identified an inhibitor that binds to Skp2 and interferes with the Skp2/p300 interaction. We show that antagonizing the Skp2/p300 interaction by the inhibitor leads to p300-mediated p53 acetylation, resulting in p53-mediated apoptosis in cancer cells, without affecting Skp2 proteolytic activity. Our results suggest that inhibition of the Skp2/p300 interaction has a great potential as a new anticancer strategy, and our Skp2 inhibitor can be developed as a chemical probe to delineate Skp2 non-proteolytic function in tumorigenesis.