Fig. 8.

Model of mevalonate and Hippo pathways regulating YAP-controlled RHAMM transcription and cancer cell motility. Mevalonate pathway regulates activity of YAP, the downstream effector of Hippo pathway, which activates transcription of RHAMM that is required for ERK activation and cancer cell migration and invasion. YAP/TEAD activates RHAMM transcription by binding to RHAMM promoter at two specific TEAD-binding sites. Mevalonate pathway promotes and simvastatin inhibits YAP activity, and consequently RHAMM transcription, ERK activation, and cancer metastasis, via modulating YAP phosphorylation and nuclear-cytoplasmic distribution. The regulation of YAP-mediated RHAMM transcription and cancer metastasis depends on geranylgeranylation, Rho GTPase activity, and actin cytoskeleton assembly, but not the canonical MST/LATS cascade.