The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth.
However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ
activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA
reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl
pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by
inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate–YAP/TAZ axis is required for
proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and
geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is
promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic
cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.
