2. Academic Validation
  3. Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization

Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization

  • Commun Biol. 2024 Nov 9;7(1):1476. doi: 10.1038/s42003-024-07067-8.
Gang Wang # 1 2,  Tianchen Peng # 3,  Liang Chen # 3,  Kangping Xiong 3,  Lingao Ju 4,  Kaiyu Qian 4,  Yi Zhang 5 6,  Yu Xiao 7,  Xinghuan Wang 8 9 10
Affiliations

Affiliations

  • 1 Department of Urology, Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. gangwang.uro@whu.edu.cn.
  • 2 Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China. gangwang.uro@whu.edu.cn.
  • 3 Department of Urology, Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 5 Euler Technology, ZGC Life Sciences Park, Beijing, China.
  • 6 Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China.
  • 7 Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China. yu.xiao@whu.edu.cn.
  • 8 Department of Urology, Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China. wangxinghuan@whu.edu.cn.
  • 9 Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. wangxinghuan@whu.edu.cn.
  • 10 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China. wangxinghuan@whu.edu.cn.
  • # Contributed equally.
PMID: 39521858 DOI: 10.1038/s42003-024-07067-8
Abstract

The progression and outcome of bladder Cancer (BLCA) are critically affected by the propensity of tumor metastasis. Our previous study revealed that activation of the mevalonate (MVA) pathway promoted migration of BLCA cells; however, the exact mechanism is unclear. Here we show that elevated expression of MVA pathway Enzymes in BLCA cells, correlating with poorer patient prognosis by analyzing single-cell and bulk-transcriptomic datasets. Inhibition of the MVA pathway, either through knockdown of farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid or simvastatin, led to a marked reduction in BLCA cell migration. Notably, this effect was reversed by administering geranylgeranyl pyrophosphate (GGPP), not farnesyl pyrophosphate (FPP) or Cholesterol, indicating the specificity of geranylgeranylation for cell motility. Moreover, we found that RhoB, a Rho GTPase family member, was identified as a key effector of the impact of the MVA pathway on BLCA metastasis. The post-translational modification of RhoB by GGPP-mediated geranylgeranylation influenced its protein stability through the ubiquitin-proteasome pathway. Additionally, overexpression of RhoB was found to block the membrane translocation of Integrin β1 in BLCA cells. In summary, our findings underscore the role of the MVA pathway in BLCA metastasis, providing insights into potential therapeutic targets of this malignancy.

Figures
Products