Editors' ChoiceCancer

Statins Inhibit YAP

Sci. Signal.  14 Jan 2014:
Vol. 7, Issue 308, pp. ec11
DOI: 10.1126/scisignal.2005067

Phosphorylation of the transcriptional coactivator YAP, frequently by Hippo pathway kinases, causes its cytoplasmic retention, thereby preventing the transcription of genes involved in proliferation. Statins are a class of drugs that prevent the synthesis of cholesterol and geranylgeranyl pyrophosphate (GGPP) by the mevanolate pathway. Originally prescribed to reduce cholesterol in patients with cardiovascular disease, statins also prevent the growth of cancer in experimental models. Wang et al. discovered that statins inhibit YAP to prevent the transcription of the gene encoding RHAMM (receptor for hyaluronan-mediated motility). RHAMM is overexpressed in diverse cancers, and overexpression of RHAMM in breast cells promotes phosphorylation of ERK (extracellular signal–regulated kinase), as well as transformation, migration, and invasion. The RHAMM promoter sequence contained binding sites for TEADs, which bind to YAP to promote transcription, and chromatin immunoprecipitation showed that YAP and TEAD bound to the promoter of RHAMM in breast cancer cells (BCCs). The mRNA or protein abundance of RHAMM was reduced in BCCs by treatment with simvastatin or knockdown of YAP or TEADs by short-hairpin RNAs. Knockdown of RHAMM, YAP, or TEADs in BCCs or treating BCCs with simvastatin inhibited the phosphorylation of ERK, migration in a transwell assay, and invasion into an artificial extracellular matrix. Treating BCCs with simvastatin increased the phosphorylation of YAP in a manner that was independent of the Hippo pathway kinases MSTs and LATs and inhibited binding of YAP to the RHAMM promoter. Treating BCCs with mevanolate or GGPP prevented the simvastatin-induced reduction in RHAMM mRNA and protein abundance and increase in the phosphorylation of YAP, whereas treating BCCs with a geranylgeranyl transferase inhibitor (GGTI) mimicked the effects of simvastatin. Treating BCCs with either simvastatin or GGTI inhibited the activity of the guanosine triphosphatase Rho, and expression of constitutively active RhoA in BCCs reversed the effects of simvastatin treatment. Inhibition of Rho increased the phosphorylation of YAP and inhibited RHAMM expression and phosphorylation of ERK. Immunoreactivity for RHAMM and YAP was increased in breast invasive ductal carcinoma, and BCC xenografts of mice treated with simvastatin showed increased phosphorylation of YAP and ERK and reduced abundance of RHAMM. Thus, statins prevent YAP-mediated transcriptional activation of RHAMM and may be therapeutically useful in breast cancer patients.

Z. Wang, Y. Wu, H. Wang, Y. Zhang, L. Mei, X. Fang, X. Zhang, F. Zhang, H. Chen, Y. Liu, Y. Jiang, S. Sun, Y. Zheng, N. Li, L. Huang, Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc. Natl. Acad. Sci. U.S.A. 111, E89–E98 (2014). [Abstract] [Full]