Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Abstract

Expression of receptor for hyaluronan-mediated motility (RHAMM), a breast cancer susceptibility gene, is tightly controlled in normal tissues but elevated in many tumors, contributing to tumorigenesis and metastases. However, how the expression of RHAMM is regulated remains elusive. Statins, inhibitors of mevalonate metabolic pathway widely used for hypercholesterolemia, have been found to also have antitumor effects, but little is known of the specific targets and mechanisms. Moreover, Hippo signaling pathway plays crucial roles in organ size control and cancer development, yet its downstream transcriptional targets remain obscure. Here we show that RHAMM expression is regulated by mevalonate and Hippo pathways converging onto Yes-associated protein (YAP)/TEAD, which binds RHAMM promoter at specific sites and controls its transcription and consequently breast cancer cell migration and invasion (BCCMI); and that simvastatin inhibits BCCMI via targeting YAP-mediated RHAMM transcription. Required for ERK phosphorylation and BCCMI, YAP-activated RHAMM transcription is dependent on mevalonate and sensitive to simvastatin, which modulate RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic localization. Further, modulation by mevalonate/simvastatin of YAP-activated RHAMM transcription requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement, but is largely independent of MST and LATS kinase activity. These findings from in vitro and in vivo investigations link mevalonate and Hippo pathways with RHAMM as a downstream effector, a YAP-transcription and simvastatin-inhibition target, and a cancer metastasis mediator; uncover a mechanism regulating RHAMM expression and cancer metastases; and reveal a mode whereby simvastatin exerts anticancer effects; providing potential targets for cancer therapeutic agents.

Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

“…Our findings provide a mechanistic explanation for such pleiotropic effects of statin on vascular cells. We found that statin repressed the OS-induced EC proliferation and inflammation, and that statin caused the reduction of YAP/TAZ activities and cytoplasmic retention of YAP/TAZ both in vitro and in vivo, similar to the findings in cancer cells (12,13). Most importantly, reconstitution of the YAP/TAZ activities blocked the statin suppressions of EC proliferation and inflammation (Fig.…”

“…Statin, a commonly used antiatherosclerotic drug, has been shown to repress YAP activity and prevent YAP-mediated transcription in tumor growth (12,13). Similar to the LS, statin treatment exerts …”

“…YAP/TAZ are retained in the cytoplasm and inactive in gene transcription when phosphorylated; in contrast, the dephosphorylated form of YAP/TAZ translocates into the nucleus to promote the target gene transcription via interactions with the transcription factor partners (e.g., TEA domain transcription factors, TEADs) (9). Many biochemical factors such as cytokines (e.g., IL-6), growth factors (e.g., EGF), and drugs (e.g., statins) have been shown to regulate YAP/TAZ activities and functional outcomes (10)(11)(12)(13). Recent studies have reported that YAP/TAZ serve as major mechanotransducers responding to extracellular biophysical cues, such as cell geometry and matrix stiffness, in modulating stem cell fate (14).…”

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

“…Interestingly, PKDs and YAP were identified as components of the intestinal stem cell signature composed of 384 unique genes (73). Supporting the notion that YAP/TAZ activation contributes to mediate long term biological responses, we showed that treatment of IEC-18 cells with cerivastatin, a potent inhibitor of YAP/TAZ activity (66,67), prevented the stimulation of DNA synthesis induced via GPCR/PKD, and knockdown of YAP/ TAZ suppressed proliferation of intestinal epithelial cells.…”

The sweet side of YAP/TAZ

“…This study highlights the notion that YAP/TAZ are atypical oncogenic molecules that, rather than being activated by genetic events, lay downstream of multiple cancer hallmarks embedded in the tumor microenvironment 3 . Our data, together with the recent observation that cholesterol biosynthesis and energy stress also regulate YAP/TAZ, [4][5][6] indicates that YAP/TAZ are activated downstream of metabolic pathways, possibly triggered by other oncogenic insults; in this view, YAP/TAZ may thus represent a general "bottleneck" for tumorigenesis, bridging information from the glucose and lipid metabolic state into cell proliferation and aggressive behaviors of cancer cells. More in general, this might open new paths to understand the crosstalk between tumor metabolism and cell signaling, to identify novel anti-YAP/TAZ compounds and to design combinatorial approaches to disable the powerful oncogenic activity of YAP/TAZ.…”