Cancer Cell International (Jan 2024)

USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer

  • Rongfu Tu,
  • Ye Kang,
  • Yiwen Pan,
  • Yanyan Da,
  • Doudou Ren,
  • Ru Zhang,
  • Zeqiong Cai,
  • Yijia Liu,
  • Jiao Xu,
  • Junpeng Ma,
  • Zhiyong Zhou,
  • Shupeng Yin,
  • Xiaozhuang Li,
  • Peng Zhang,
  • Qi Zhang,
  • Jingchao Wang,
  • Xinlan Lu,
  • Chengsheng Zhang

DOI
https://doi.org/10.1186/s12935-024-03224-5
Journal volume & issue
Vol. 24, no. 1
pp. 1 – 14

Abstract

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Abstract Background Gastric cancer is a highly prevalent cancer type and the underlying molecular mechanisms are not fully understood. Ubiquitin-specific peptidase (USP) 29 has been suggested to regulate cell fate in several types of cancer, but its potential role in gastric carcinogenesis remains unclear. Methods The expression of USP29 in normal and gastric cancer tissues was analyzed by bioinformatics analysis, immunohistochemistry and immunoblot. Gene overexpression, CRISPR-Cas9 technology, RNAi, and Usp29 knockout mice were used to investigate the roles of USP29 in cell culture, xenograft, and benzo[a]pyrene (BaP)-induced gastric carcinogenesis models. We then delineated the underlying mechanisms using mass spectrometry, co-immunoprecipitation (Co-IP), immunoblot, ubiquitination assay, chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and luciferase assays. Results In this study, we found that USP29 expression was significantly upregulated in gastric cancers and associated with poor patient survival. Ectopic expression of USP29 promoted, while depletion suppressed the tumor growth in vitro and in vivo mouse model. Mechanistically, transcription factor far upstream element binding protein 1 (FUBP1) directly activates USP29 gene transcription, which then interacts with and stabilizes aurora kinase B (AURKB) by suppressing K48-linked polyubiquitination, constituting a FUBP1-USP29-AURKB regulatory axis that medicates the oncogenic role of USP29. Importantly, systemic knockout of Usp29 in mice not only significantly decreased the BaP-induced carcinogenesis but also suppressed the Aurkb level in forestomach tissues. Conclusions These findings uncovered a novel FUBP1-USP29-AURKB regulatory axis that may play important roles in gastric carcinogenesis and tumor progression, and suggested that USP29 may become a promising drug target for cancer therapy.

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