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Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations
Published on: November 7, 2019
CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and
Youzhou Sang1, Yanxin Li2, Yingwen Zhang2
1State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
Abstract:
Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.
Insights
Researchers discovered a new pathway involving CDK5 and TRIM59 that drives glioblastoma (GBM) growth. Inhibiting this CDK5/TRIM59 axis suppressed tumor growth, suggesting a potential new therapy for GBM patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma (GBM) remains largely incurable despite advances in adjuvant therapies, highlighting the critical need for novel therapeutic strategies.
- Cyclin-dependent kinase 5 (CDK5) is implicated in GBM pathogenesis, but its precise role in promoting tumor growth is not fully understood.
- Identifying the molecular mechanisms underlying CDK5's function in GBM is essential for developing targeted treatments.
Purpose of the Study:
- To elucidate the mechanism by which CDK5 contributes to glioblastoma tumorigenicity.
- To identify downstream targets of CDK5 involved in GBM progression.
- To evaluate the therapeutic potential of targeting the CDK5 signaling pathway in GBM.
Main Methods:
- Investigated the interaction between CDK5 and TRIM59 using biochemical assays.
- Utilized phosphorylation site mapping and protein-protein interaction studies to define the regulatory mechanism.
- Assessed the impact of inhibiting the CDK5/TRIM59 axis on GBM cell lines and intracranial tumor models.
Main Results:
- Identified TRIM59 as a direct substrate of EGFR-activated CDK5, with phosphorylation occurring at serine 308.
- Demonstrated that CDK5-mediated phosphorylation of TRIM59 facilitates its nuclear translocation via PIN1 and importin α5.
- Showed that nuclear TRIM59 promotes GBM tumorigenicity by inducing the degradation of the tumor suppressor macroH2A1, leading to STAT3 activation. Inhibition of this axis suppressed tumor growth.
- Found that the expression levels of pathway components correlate with clinical prognosis in GBM patients.
Conclusions:
- The CDK5/TRIM59 signaling axis is a key driver of glioblastoma tumorigenicity.
- Targeting CDK5-mediated phosphorylation of TRIM59 and subsequent downstream events represents a promising therapeutic strategy for GBM.
- The identified pathway components serve as potential prognostic biomarkers for GBM.
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