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      The mevalonate pathway promotes the metastasis of osteosarcoma by regulating YAP1 activity via RhoA

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          Abstract

          Osteosarcoma is the most common malignant bone tumour, and the metastasis of osteosarcoma is an important cause of death. Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy. In this study, we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism. First, we found that the key rate-limiting enzyme of mevalonate signalling, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was highly expressed in osteosarcoma cells, and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells. Next, we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells. We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization. Moreover, we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA. Finally, we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells, as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice. Taken together, our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA. Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.

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          Most cited references44

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          YAP/TAZ at the Roots of Cancer.

          YAP and TAZ are highly related transcriptional regulators pervasively activated in human malignancies. Recent work indicates that, remarkably, YAP/TAZ are essential for cancer initiation or growth of most solid tumors. Their activation induces cancer stem cell attributes, proliferation, chemoresistance, and metastasis. YAP/TAZ are sensors of the structural and mechanical features of the cell microenvironment. A number of cancer-associated extrinsic and intrinsic cues conspire to overrule the YAP-inhibiting microenvironment of normal tissues, including changes in mechanotransduction, inflammation, oncogenic signaling, and regulation of the Hippo pathway. Addiction to YAP/TAZ thus potentially represents a central cancer vulnerability that may be exploited therapeutically.
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            The Hippo Signaling Pathway in Development and Disease

            The Hippo signaling pathway regulates diverse physiological processes, and its dysfunction has been implicated in an increasing number of human diseases, including cancer. Here, we provide an updated review of the Hippo pathway; discuss its roles in development, homeostasis, regeneration, and diseases; and highlight outstanding questions for future investigation and opportunities for Hippo-targeted therapies.
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              The interplay between cell signalling and the mevalonate pathway in cancer.

              The mevalonate (MVA) pathway is an essential metabolic pathway that uses acetyl-CoA to produce sterols and isoprenoids that are integral to tumour growth and progression. In recent years, many oncogenic signalling pathways have been shown to increase the activity and/or the expression of MVA pathway enzymes. This Review summarizes recent advances and discusses unique opportunities for immediately targeting this metabolic vulnerability in cancer with agents that have been approved for other therapeutic uses, such as the statin family of drugs, to improve outcomes for cancer patients.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                21 November 2020
                May 2022
                21 November 2020
                : 9
                : 3
                : 741-752
                Affiliations
                [1]Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China
                Author notes
                []Corresponding author. No.1 YouYi Road, Yu Zhong District, Chongqing 400016, PR China. jdm201296@ 123456hospital.cqmu.edu.cn
                Article
                S2352-3042(20)30140-9
                10.1016/j.gendis.2020.11.009
                9243346
                35782968
                2fdf095d-af6b-4a68-999b-0a2a9d4907f2
                © 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 21 August 2020
                : 21 October 2020
                : 16 November 2020
                Categories
                Full Length Article

                metastasis,mevalonate pathway,osteosarcoma,rhoa,yap1
                metastasis, mevalonate pathway, osteosarcoma, rhoa, yap1

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