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Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Jan 07; Vol. 111 (1), pp. E89-98. Date of Electronic Publication: 2013 Dec 23. - Publication Year :
- 2014
-
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.
- Subjects :
- Actins chemistry
Animals
Base Sequence
Cell Line, Tumor
Cell Movement
Extracellular Signal-Regulated MAP Kinases metabolism
Female
HEK293 Cells
Hippo Signaling Pathway
Humans
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Neoplasm Metastasis
Neoplasm Transplantation
Phosphorylation
Signal Transduction physiology
Simvastatin chemistry
Transcription Factors
YAP-Signaling Proteins
Adaptor Proteins, Signal Transducing metabolism
Breast Neoplasms metabolism
Extracellular Matrix Proteins metabolism
Gene Expression Regulation, Neoplastic
Hyaluronan Receptors metabolism
Mevalonic Acid metabolism
Phosphoproteins metabolism
Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 111
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 24367099
- Full Text :
- https://doi.org/10.1073/pnas.1319190110