title: 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.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wu
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wang
authors.forename: Yangqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Xuexun
authors.initials: X
authors.lastname: Fang
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Shengnan
authors.initials: S
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
mesh_terms: D000199:Actins / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019821:Simvastatin / Q000737:chemistry; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C098946:hyaluronan-mediated motility receptor; D019821:Simvastatin; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D008798:Mevalonic Acid
keywords: actin assembly; crosstalk; metabolism; oncogene; tumor suppressor