STUB1-SMYD2 Axis Regulates Drug Resistance in Glioma cells
Kailing Pan1, Bin Hu2, Lude Wang1
1Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Zhejiang Province, Jinhua, 321000, China.
Abstract:
SET and MYND domain-containing protein 2 (SMYD2) is an important epigenetic regulator that methylates histone and non-histone proteins. The study aimed to investigate the oncogenic role of SMYD2 in gliomas and explore its degradation mechanism induced by cisplatin. Tumor tissue microarray of 441 patients with glioma was collected for SMYD2 immunohistochemical staining. Kaplan-Meier survival curves were constructed using the overall survival values. mRNA-sequencing analysis was performed for understanding the downstream mechanisms mediated by SMYD2. The half-inhibitory concentrations (IC50) of temozolomide and cisplatin in AZ505-treated and control cells were calculated. The potential E3 ubiquitin ligase of SMYD2 was predicted in UbiBrowser and confirmed by a knockdown test. The effect of SMYD2 and its E3 ligase on apoptosis and migration of glioma cells was determined via cell-function assays. High SMYD2 expression correlated with a high WHO stage (P = 0.004) and a low survival probability (P = 0.012). The inhibition of SMYD2 suppressed the process of epithelial to mesenchymal transition (EMT) by downregulating the expression of Collagen 1A1 (COL1A1). AZ505 treatment significantly increased the drug sensitivity of glioma cells. SMYD2 expression was markedly reduced by cisplatin treatment via STIP1 Homology And U-Box Containing Protein 1 (STUB1)-mediated degradation. The knockdown of STUB1 could partly reverse the cell function impairment induced by cisplatin. Our findings suggested that SMYD2 could be a potential drug target for the treatment of gliomas, and STUB1-mediated degradation of SMYD2 plays an important role in reversing chemotherapy resistance in patients with gliomas.
Insights
SET and MYND domain-containing protein 2 (SMYD2) promotes glioma progression and is linked to poor survival. Cisplatin treatment degrades SMYD2 via STUB1, enhancing chemotherapy sensitivity and offering a potential therapeutic strategy for glioma patients.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- SET and MYND domain-containing protein 2 (SMYD2) is an epigenetic regulator involved in cancer.
- Its role in glioma and response to chemotherapy requires further investigation.
Purpose of the Study:
- To investigate the oncogenic role of SMYD2 in gliomas.
- To explore the mechanism of SMYD2 degradation by cisplatin and its therapeutic implications.
Main Methods:
- Immunohistochemical staining of SMYD2 in 441 glioma tissues.
- Kaplan-Meier survival analysis and mRNA-sequencing.
- In vitro assays including drug sensitivity, apoptosis, migration, and E3 ligase identification (STUB1).
Main Results:
- High SMYD2 expression correlated with advanced WHO stage and reduced survival in glioma patients.
- SMYD2 inhibition suppressed epithelial-mesenchymal transition (EMT) and Collagen 1A1 (COL1A1) expression.
- Cisplatin treatment induced SMYD2 degradation via STIP1 Homology And U-Box Containing Protein 1 (STUB1), increasing drug sensitivity and reversing cisplatin-induced cell function impairment.
Conclusions:
- SMYD2 is an oncogenic driver in gliomas and a potential therapeutic target.
- STUB1-mediated degradation of SMYD2 is a key mechanism in reversing chemotherapy resistance in glioma.
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