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Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility.
Proc Natl Acad Sci U S A. 2014 Jan 07; 111(1):E89-98.PN

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+Show Affiliations

School of Life Sciences, Tsinghua University, Beijing 100084, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24367099

Citation

Wang, Zhongyuan, et al. "Interplay of Mevalonate and Hippo Pathways Regulates RHAMM Transcription Via YAP to Modulate Breast Cancer Cell Motility." Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 1, 2014, pp. E89-98.
Wang Z, Wu Y, Wang H, et al. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci USA. 2014;111(1):E89-98.
Wang, Z., Wu, Y., Wang, H., Zhang, Y., Mei, L., Fang, X., Zhang, X., Zhang, F., Chen, H., Liu, Y., Jiang, Y., Sun, S., Zheng, Y., Li, N., & Huang, L. (2014). Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proceedings of the National Academy of Sciences of the United States of America, 111(1), E89-98. https://doi.org/10.1073/pnas.1319190110
Wang Z, et al. Interplay of Mevalonate and Hippo Pathways Regulates RHAMM Transcription Via YAP to Modulate Breast Cancer Cell Motility. Proc Natl Acad Sci USA. 2014 Jan 7;111(1):E89-98. PubMed PMID: 24367099.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. AU - Wang,Zhongyuan, AU - Wu,Yanping, AU - Wang,Haifeng, AU - Zhang,Yangqing, AU - Mei,Lin, AU - Fang,Xuexun, AU - Zhang,Xudong, AU - Zhang,Fang, AU - Chen,Hongbo, AU - Liu,Ying, AU - Jiang,Yuyang, AU - Sun,Shengnan, AU - Zheng,Yi, AU - Li,Na, AU - Huang,Laiqiang, Y1 - 2013/12/23/ PY - 2013/12/25/entrez PY - 2013/12/25/pubmed PY - 2014/3/13/medline KW - actin assembly KW - crosstalk KW - metabolism KW - oncogene KW - tumor suppressor SP - E89 EP - 98 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 111 IS - 1 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/24367099/Interplay_of_mevalonate_and_Hippo_pathways_regulates_RHAMM_transcription_via_YAP_to_modulate_breast_cancer_cell_motility_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=24367099 DB - PRIME DP - Unbound Medicine ER -