Geranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration

Abstract

Protein geranylgeranylation (GGylation) is an important biochemical process for many cellular signaling molecules. Previous studies have shown that GGylation is essential for cell survival in many types of cancer. However, the molecular mechanism mediating the cell survival effect remains elusive. In this report, we show that the Hippo pathway mediates GGylation-dependent cell proliferation and migration in breast cancer cells. Blockade of GGylation enhanced phosphorylation of Mst1/2 and Lats1, and inhibited YAP and TAZ activity and the Hippo-YAP/TAZ pathway-dependent transcription. The effect of GGylation blockade on inhibition of breast cancer cell proliferation and migration is dependent on the Hippo-YAP/TAZ signaling, in which YAP appears to regulate cell proliferation and TAZ to regulate cell migration. Furthermore, GGylation-dependent cell proliferation is correlated with the activity of YAP/TAZ in breast cancer cells. Finally, Gγ and RhoA are the GGylated proteins that may transduce GGylation signals to the Hippo-YAP/TAZ pathway. Taken together, our studies have demonstrated that the Hippo-YAP/TAZ pathway is essential for GGylation-dependent cancer cell proliferation and migration.

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“…An inhibitor of the enzyme 3-hydroxyl-3-methylglutaryl-CoA (HMG-CoA) reductase converts HMG-CoA to mevalonic acid, causing marked cytoplasmic accumulation of YAP and TAZ (Figure 2D). Mevalonic acid is a precursor of geranylgeranyl pyrophosphate, which promotes G βγ protein and Rho GTPase activity though geranylgeranylation, enhancing YAP and TAZ activity [88, 89]. Mevalonate-mediated YAP and TAZ activation increases the expression of the receptor for hyaluronan-mediated motility (RHAMM), contributing to the tumorigenesis and metastasis of many tumors [90].…”

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“…Statin treatment caused cytoplasmic relocalization and inhibition of YAP/TAZ in several cancer types and a reduction of cancer stem cell growth and tumor xenografts (Sorrentino et al, 2014;Wang et al, 2014;Li et al, 2015). Bisphosphonates and geranylgeranyl transferase 1 inhibitors also target the mevalonate pathways and have similar effects on inhibiting YAP and TAZ (Sorrentino et al, 2014;Mi et al, 2015).…”