TRIM21-Mediated Ubiquitination and Phosphorylation of ERK1/2 Promotes Cell Proliferation and Drug Resistance in Pituitary Adenomas
Academic Background
Pituitary adenomas (PAs) are common intracranial tumors with complex pathogenesis, often accompanied by abnormal hormone secretion. Although various treatments, such as dopamine agonists (DAs), are currently available, some patients exhibit drug resistance, leading to suboptimal therapeutic outcomes. Therefore, identifying new therapeutic targets and strategies has become a focal point of current research.
The TRIM family of proteins plays a crucial role in cell proliferation and tumor drug resistance. However, their role in pituitary adenomas remains poorly understood. Specifically, TRIM21, an E3 ubiquitin ligase, is known to regulate substrate protein functions through ubiquitination in various tumors, but its specific mechanisms in pituitary adenomas are still unclear. This study aims to explore the role of TRIM21 in pituitary adenoma cell proliferation and drug resistance and to elucidate its molecular mechanisms through the regulation of the ERK1/2 signaling pathway.
Source of the Paper
This paper was co-authored by Yanting Liu, Fang Liu, Chuanbao Li, and others from the Pituitary Tumor Center, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The study was published in March 2025 in the journal Neuro-Oncology, titled “TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas.”
Research Process and Results
1. CRISPR Screening Identifies the Role of TRIM21 in Pituitary Adenomas
The study began with CRISPR-Cas9 screening, constructing an sgRNA library targeting TRIM family genes and infecting GH3 and MMQ pituitary adenoma cell lines. Through in vitro and in vivo experiments, the research team found that the absence of TRIM21 significantly inhibited cell proliferation and increased sensitivity to the dopamine agonist Cabergoline (Cab). Further experiments showed that overexpression of TRIM21 enhanced cell proliferation and drug resistance, while knockout of TRIM21 suppressed cell proliferation and increased drug sensitivity.
2. TRIM21 Promotes Cell Proliferation and Drug Resistance by Activating the ERK1/2 Signaling Pathway
To explore the mechanisms by which TRIM21 regulates cell proliferation and drug resistance, the research team conducted transcriptome analysis and found that the absence of TRIM21 significantly reduced the activity of the MAPK, RAS, and PI3K-AKT signaling pathways. Further immunoblotting analysis revealed that overexpression of TRIM21 significantly enhanced ERK1/2 phosphorylation, while knockout of TRIM21 suppressed ERK1/2 phosphorylation. Additionally, in a nude mouse xenograft model, overexpression of TRIM21 increased ERK1/2 phosphorylation levels, while knockout of TRIM21 reduced ERK1/2 phosphorylation levels.
3. TRIM21 Interacts with ERK1/2 Through the PRY-SPRY Domain
To elucidate the molecular mechanisms by which TRIM21 regulates the ERK1/2 signaling pathway, the research team performed co-immunoprecipitation (Co-IP) and mass spectrometry analysis, revealing that TRIM21 interacts with ERK1/2 through its PRY-SPRY domain. Further experiments demonstrated that TRIM21 promotes ERK1/2 ubiquitination through K27-linked polyubiquitination, thereby enhancing the interaction between ERK1/2 and MEK1/2 and subsequently promoting ERK1/2 phosphorylation.
4. Upregulation of TRIM21 in Dopamine-Resistant Pituitary Adenomas
The research team also found that TRIM21 is upregulated in dopamine-resistant pituitary adenomas and is positively correlated with ERK1/2 phosphorylation levels. Through drug screening, the team identified Fimepinostat and Quisinostat as compounds that can reduce TRIM21 protein levels, inhibit tumor progression, and increase drug sensitivity.
Research Conclusions
This study reveals that TRIM21 promotes ERK1/2 phosphorylation through K27-linked polyubiquitination, thereby enhancing pituitary adenoma cell proliferation and drug resistance. Additionally, the study found that TRIM21 is upregulated in dopamine-resistant pituitary adenomas, and inhibition of TRIM21 can enhance drug sensitivity. Therefore, TRIM21 may serve as a new therapeutic target for pituitary adenomas, and inhibiting TRIM21 could be a potential treatment strategy.
Research Highlights
- TRIM21 as a New Therapeutic Target: This study is the first to reveal the critical role of TRIM21 in pituitary adenoma cell proliferation and drug resistance, providing a theoretical basis for developing new treatment strategies.
- K27-Linked Polyubiquitination Mechanism: The study found that TRIM21 regulates ERK1/2 phosphorylation through K27-linked polyubiquitination, offering new insights into the regulatory mechanisms of the ERK1/2 signaling pathway.
- Drug Screening Identifies New Compounds: Through drug screening, the research team identified Fimepinostat and Quisinostat as effective compounds that reduce TRIM21 protein levels and inhibit tumor progression, providing potential candidates for clinical trials.
Research Significance
This study not only deepens our understanding of the role of TRIM21 in pituitary adenomas but also provides important experimental evidence for developing new treatment strategies. As an E3 ubiquitin ligase, TRIM21’s regulatory mechanisms in the ERK1/2 signaling pathway may have broader implications in other tumors. Additionally, the discovery of Fimepinostat and Quisinostat offers new drug options for the clinical treatment of pituitary adenomas.
Other Valuable Information
The study also found that TRIM21 is widely expressed in various types of tumors, and high levels of TRIM21 are associated with poor patient prognosis. This suggests that TRIM21 may play an important regulatory role in other tumors, and future research could further explore the functions and mechanisms of TRIM21 in other cancers.
This study provides new insights and potential drug targets for the treatment of pituitary adenomas, offering significant scientific and clinical value.