2. Academic Validation
  3. TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by targeting the splicing factor NONO

TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by targeting the splicing factor NONO

  • J Exp Clin Cancer Res. 2024 Feb 2;43(1):39. doi: 10.1186/s13046-024-02964-6.
Yike Chen # 1 2,  Xiaohui Xu # 1 2,  Kaikai Ding 3,  Tianchi Tang 1 2,  Feng Cai 1 2,  Haocheng Zhang 1 2,  Zihang Chen 1 2,  Yangjian Qi 1 2,  Zaixiang Fu 1 2,  Ganggui Zhu 1 2,  Zhangqi Dou 1 2,  Jinfang Xu 1 2,  Gao Chen 1 2,  Qun Wu 4 5,  Jianxiong Ji 6 7,  Jianmin Zhang 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China.
  • 2 Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310000, Zhejiang, P. R. China.
  • 3 Department of Radiation Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China.
  • 4 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China. 2192010@zju.edu.cn.
  • 5 Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310000, Zhejiang, P. R. China. 2192010@zju.edu.cn.
  • 6 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China. jijx@zju.edu.cn.
  • 7 Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310000, Zhejiang, P. R. China. jijx@zju.edu.cn.
  • 8 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China. zjm135@zju.edu.cn.
  • 9 Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310000, Zhejiang, P. R. China. zjm135@zju.edu.cn.
  • 10 Brain Research Institute, Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China. zjm135@zju.edu.cn.
  • 11 MOE Frontier Science Center for Brain Science & Brain-Machine Integration Zhejiang University, Hangzhou, 310000, Zhejiang, P. R. China. zjm135@zju.edu.cn.
  • # Contributed equally.
PMID: 38303029 DOI: 10.1186/s13046-024-02964-6
Abstract

Background: Ubiquitination plays an important role in proliferating and invasive characteristic of glioblastoma (GBM), similar to many other cancers. Tripartite motif 25 (TRIM25) is a member of the TRIM family of proteins, which are involved in tumorigenesis through substrate ubiquitination.

Methods: Difference in TRIM25 expression levels between nonneoplastic brain tissue samples and primary glioma samples was demonstrated using publicly available glioblastoma database, immunohistochemistry, and western blotting. TRIM25 knockdown GBM cell lines (LN229 and U251) and patient derived GBM stem-like cells (GSCs) GBM#021 were used to investigate the function of TRIM25 in vivo and in vitro. Co-immunoprecipitation (Co-IP) and mass spectrometry analysis were performed to identify NONO as a protein that interacts with TRIM25. The molecular mechanisms underlying the promotion of GBM development by TRIM25 through NONO were investigated by RNA-seq and validated by qRT-PCR and western blotting.

Results: We observed upregulation of TRIM25 in GBM, correlating with enhanced glioblastoma cell growth and invasion, both in vitro and in vivo. Subsequently, we screened a panel of proteins interacting with TRIM25; mass spectrometry and co-immunoprecipitation revealed that NONO was a potential substrate of TRIM25. TRIM25 knockdown reduced the K63-linked ubiquitination of NONO, thereby suppressing the splicing function of NONO. Dysfunctional NONO resulted in the retention of the second intron in the pre-mRNA of PRMT1, inhibiting the activation of the PRMT1/c-Myc pathway.

Conclusions: Our study demonstrates that TRIM25 promotes glioblastoma cell growth and invasion by regulating the PRMT1/c-Myc pathway through mediation of the splicing factor NONO. Targeting the E3 Ligase activity of TRIM25 or the complex interactions between TRIM25 and NONO may prove beneficial in the treatment of GBM.

Keywords

NONO; Splicing efficiency; TRIM25; Ubiquitination; c-MYC pathway.

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