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Identification and verification of the temozolomide resistance feature gene DACH1 in gliomas
Qiang Gu1, Lang Li1, Jiahao Yao1
1Harbin Medical University, Harbin, China.
Introduction:
The most important chemotherapy treatment for glioma patients is temozolomide. However, the development of drug resistance severely restricts the use of temozolomide. Therefore, elucidating the mechanism of temozolomide resistance, enhancing temozolomide sensitivity, and extending patient survival are urgent tasks for researchers.
Methods:
Temozolomide resistance hub differential genes were identified using differential analysis and protein interaction analysis from the GEO datasets (GSE100736 and GSE113510). These genes were further studied in glioma patients treated with temozolomide in the TCGA and CGGA databases. Patients from the mRNAseq_325 dataset (CGGA) were considered as the training set to construct a risk model for predicting glioma sensitivity to temozolomide, while patients from the mRNAseq_693 dataset (CGGA) and TCGA-GBM dataset were considered as the validation set to evaluate the performance of models. PCR and western blot were performed to determine the difference in expression of the feature gene DACH1 between glioma cells and temozolomide-resistant glioma cells. The alterations in the sensitivity of tumor cells to temozolomide were also observed after DACH1 was silenced. The patients were then divided into two groups based on the expression of DACH1, and the differences in patient survival rates, molecular pathway activation, and level of immune infiltration were compared.
Results:
Based on four signature genes (AHR, DACH1, MGMT, and YAP1), a risk model for predicting glioma sensitivity to temozolomide was constructed, and the results of timeROC in both the training and validation sets showed that the model had good predictive performance. The expression of the signature gene DACH1 was significantly downregulated in temozolomide-resistant cells, according to the results of the PCR and western blot experiments. The sensitivity of tumor cells to temozolomide was significantly reduced after DACH1 was silenced. DACH1 probably regulates temozolomide resistance in glioblastoma through the transcriptional dysregulation in cancer and ECM.
Discussion:
This study constructs a risk model that can predict glioma susceptibility to temozolomide and validates the function of the feature gene DACH1, which provides a promising target for the research of temozolomide resistance.
Insights
This study identifies DACH1 as a key gene in temozolomide resistance in glioma. Silencing DACH1 reduces drug sensitivity, offering a potential therapeutic target to improve glioma treatment outcomes.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Temozolomide is a critical chemotherapy for glioma patients.
- Drug resistance to temozolomide significantly limits its clinical efficacy.
- Understanding resistance mechanisms is crucial for improving glioma treatment.
Purpose of the Study:
- To identify genes associated with temozolomide resistance in glioma.
- To develop a predictive model for glioma sensitivity to temozolomide.
- To investigate the role of the gene DACH1 in temozolomide resistance.
Main Methods:
- Differential gene expression analysis and protein-protein interaction analysis on GEO datasets (GSE100736, GSE113510).
- Construction and validation of a risk model using TCGA and CGGA databases.
- Experimental validation of DACH1 expression and function using PCR, Western blot, and gene silencing in glioma cells.
Main Results:
- A four-gene signature risk model (AHR, DACH1, MGMT, YAP1) demonstrated good predictive performance for temozolomide sensitivity.
- DACH1 was significantly downregulated in temozolomide-resistant glioma cells.
- DACH1 silencing reduced tumor cell sensitivity to temozolomide, suggesting its role in resistance.
Conclusions:
- The developed risk model effectively predicts glioma susceptibility to temozolomide.
- DACH1 plays a significant role in regulating temozolomide resistance in glioblastoma.
- DACH1 represents a promising therapeutic target for overcoming temozolomide resistance.
