2. Academic Validation
  3. USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer

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

  • Cancer Cell Int. 2024 Jan 17;24(1):33. doi: 10.1186/s12935-024-03224-5.
Rongfu Tu # 1,  Ye Kang # 2,  Yiwen Pan # 3,  Yanyan Da # 4 5 6 7,  Doudou Ren 2,  Ru Zhang 2,  Zeqiong Cai 2,  Yijia Liu 3,  Jiao Xu 3,  Junpeng Ma 4 5 6 7,  Zhiyong Zhou 4 5 6 7,  Shupeng Yin 4 5 6 7,  Xiaozhuang Li 4 5 6 7,  Peng Zhang 4 5 6 7,  Qi Zhang 8,  Jingchao Wang 9,  Xinlan Lu 10,  Chengsheng Zhang 11 12 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Cancer Precision Medicine, The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Building 21, Xi'an, China. rongfutu@xjtu.edu.cn.
  • 2 Department of Cancer Precision Medicine, The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Building 21, Xi'an, China.
  • 3 Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China.
  • 4 Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.
  • 5 Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie, Nanchang, 330006, China.
  • 6 Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.
  • 7 Department of Medical Genetics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 DongYue Dadao, Nanchang, 330209, China.
  • 8 Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, 518055, China.
  • 10 Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
  • 11 Department of Cancer Precision Medicine, The MED-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Building 21, Xi'an, China. cszhang99@126.com.
  • 12 Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China. cszhang99@126.com.
  • 13 Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China. cszhang99@126.com.
  • 14 Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie, Nanchang, 330006, China. cszhang99@126.com.
  • 15 Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China. cszhang99@126.com.
  • 16 Department of Medical Genetics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 DongYue Dadao, Nanchang, 330209, China. cszhang99@126.com.
  • # Contributed equally.
PMID: 38233848 DOI: 10.1186/s12935-024-03224-5
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.

Keywords

AURKB; FUBP1; Gastric Cancer; Targeted therapy; USP29.

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