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

作者全名："Du, Xing; Ou, Yunsheng; Zhang, Muzi; Li, Kai; Huang, Wei; Jiang, Dianming"

作者地址："[Du, Xing; Ou, Yunsheng; Zhang, Muzi; Li, Kai; Huang, Wei; Jiang, Dianming] Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 1, Chongqing 400016, Peoples R China"

通信作者："Jiang, DM (通讯作者)，1 YouYi Rd, Chongqing 400016, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000805331400015

JCR分区：Q1

影响因子：6.8

年份：2022

卷号：9

期号：3

开始页：741

结束页：752

文献类型：Article

关键词：Metastasis; Mevalonate pathway; Osteosarcoma; RhoA; YAP1

摘要："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. Copyright (C) 2020, Chongqing Medical University. Production and hosting by Elsevier B.V."

基金机构：Natural Science Foundation of Chongqing

基金资助正文：This work was supported by the Natural Science Foundation of Chongqing (No.cstc2019jcyj-msxmX0358).