The MED12/Cyclin C Interface as a Therapeutic Target in Oncogenic Wnt/Beta‐catenin signaling (LB285)

CDK8 is a colorectal cancer oncoprotein whose amplification-dependent overexpression identifies a significant subset of colorectal cancer patients with poor prognosis. Mechanistically, Cyclin C (CycC)-dependent CDK8 kinase drives tumorigenesis by regulating beta-catenin transcriptional activity. Accordingly, inhibition of CDK8 kinase function offers a promising therapeutic approach to CDK8-overexpressing colorectal cancers. CDK8/CycC, along MED12 and MED12, comprise a discrete 4-subunit “kinase” module within Mediator, a conserved multiprotein interface between gene-specific transcription factors and RNA Polymerase II. Our studies reveal that beta-catenin binds directly to MED12, which in turn activates CycC-dependent CDK8 kinase activity and beta-catenin target gene induction. Notably, we found that MED12 activates CDK8 through its direct interaction with an uncharacterized CycC surface groove that is phylogenetically conserved among CycC family members, but absent from cell cycle-type cyclins. We employ...