YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) accumulate in the nucleus and promote gene transcription when the Hippo signalling pathway is inactivated and in response to tension. Sorrentino et al. now show that the sterol regulatory element-binding protein (SREBP)–mevalonate pathway also promotes the activity of these transcriptional co-activators.

Credit: CORBIS

YAP and TAZ favour cell proliferation and organ growth and they are often aberrantly stabilized and activated in human cancers. Sorrentino et al. screened 640 compounds for their ability to sequester YAP and TAZ in the cytoplasm of a breast cancer cell line, thus inactivating them. Statins (drugs that lower cholesterol levels) had the strongest effect, and the authors analysed cerivastatin and simvastatin further.

Statins inhibit HMG-CoA reductase (HMGCR), which catalyses the production of mevalonic acid in the mevalonate (cholesterol biosynthesis) pathway. Inhibiting the mevalonate pathway in human cancer cell lines with cerivastatin or simvastatin caused YAP and TAZ to accumulate in the cytoplasm and inhibited their transcriptional activity; their nuclear localization was restored by the addition of mevalonic acid. The transcription of enzymes in the mevalonate pathway is positively controlled by SREBPs, and the authors found that activating or inhibiting SREBPs increased or decreased, respectively, the activity of YAP and TAZ by altering their nuclear localization. Thus, a SREBP–mevalonate pathway is required for YAP and TAZ activity.

Looking downstream of HMGCR in the mevalonate pathway, Sorrentino et al. observed that globally inhibiting the transfer of geranylgeranyl pyrophosphate (GGPP) to its targets mimicked the effects of statins. The geranylgeranylation of RHO GTPases facilitates their localization at the plasma membrane and hence their activation. Cerivastatin prevented the membrane localization of RHOA, which was restored by the addition of GGPP. Thus, the mevalonate pathway generates GGPP and seems to activate RHO GTPases to promote YAP and TAZ nuclear localization. Importantly, although RHO GTPases have been shown to control YAP and TAZ activity by influencing the actin cytoskeleton, data here suggest that they can also activate them independently of the cytoskeleton.

Finally, the authors assessed the biological relevance of their findings. In cultured cells, cerivastatin had anti-proliferative and apoptotic effects, which were blocked by the expression of constitutively active YAP. In Drosophila melanogaster, simvastatin rescued eye overgrowth that was induced by the YAP and TAZ orthologue Yki, as did silencing the enzyme required to transfer GGPP to targets. Also of note, the authors revealed that oncogenic p53 can activate YAP and TAZ in breast cancer cells through its ability to act as a positive transcription factor for SREBPs, and hence stimulate the mevalonate pathway.

the nuclear localization and activity of YAP and TAZ can also be promoted by metabolic cues

In short, this study shows that the nuclear localization and activity of YAP and TAZ can also be promoted by metabolic cues and reveals that RHO GTPases may regulate these factors independently of the cytoskeleton. It also places oncogenic p53 upstream of YAP and TAZ in promoting cancer progression.