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A Screening of Epigenetic Therapeutic Targets for Non-Small Cell Lung Cancer Reveals PADI4 and KDM6B as Promising
Jéssika Cristina Chagas Lesbon1, Taismara Kustro Garnica1, Pedro Luiz Porfírio Xavier1
1Laboratory of Comparative and Translational Oncology, Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Duque de Caxias, 225-Jardim Elite, Pirassununga 13635-900, SP, Brazil.
Abstract:
Despite advances in diagnostic and therapeutic approaches for lung cancer, new therapies targeting metastasis by the specific regulation of cancer genes are needed. In this study, we screened a small library of epigenetic inhibitors in non-small-cell lung cancer (NSCLC) cell lines and evaluated 38 epigenetic targets for their potential role in metastatic NSCLC. The potential candidates were ranked by a streamlined approach using in silico and in vitro experiments based on publicly available databases and evaluated by real-time qPCR target gene expression, cell viability and invasion assays, and transcriptomic analysis. The survival rate of patients with lung adenocarcinoma is inversely correlated with the gene expression of eight epigenetic targets, and a systematic review of the literature confirmed that four of them have already been identified as targets for the treatment of NSCLC. Using nontoxic doses of the remaining inhibitors, KDM6B and PADI4 were identified as potential targets affecting the invasion and migration of metastatic lung cancer cell lines. Transcriptomic analysis of KDM6B and PADI4 treated cells showed altered expression of important genes related to the metastatic process. In conclusion, we showed that KDM6B and PADI4 are promising targets for inhibiting the metastasis of lung adenocarcinoma cancer cells.
Insights
New research identifies KDM6B and PADI4 as promising targets for inhibiting lung cancer metastasis. These epigenetic targets show potential for developing novel therapies against metastatic non-small-cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Lung cancer, particularly non-small-cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality.
- Current treatments face limitations, highlighting the need for novel therapeutic strategies targeting cancer metastasis.
- Epigenetic modifications play a crucial role in cancer progression and metastasis.
Purpose of the Study:
- To identify novel epigenetic targets for inhibiting metastasis in non-small-cell lung cancer (NSCLC).
- To evaluate the potential of specific epigenetic inhibitors in reducing the invasive and migratory capabilities of lung cancer cells.
Main Methods:
- Screening of an epigenetic inhibitor library in NSCLC cell lines.
- In silico and in vitro validation including real-time qPCR, cell viability, invasion assays, and transcriptomic analysis.
- Correlation analysis between gene expression of epigenetic targets and patient survival rates.
Main Results:
- Eight epigenetic targets showed an inverse correlation between their gene expression and patient survival in lung adenocarcinoma.
- KDM6B and PADI4 were identified as key targets affecting the invasion and migration of metastatic lung cancer cells at non-toxic doses.
- Transcriptomic analysis revealed altered expression of metastasis-related genes following KDM6B and PADI4 inhibition.
Conclusions:
- KDM6B and PADI4 are promising therapeutic targets for inhibiting lung adenocarcinoma metastasis.
- Targeting KDM6B and PADI4 may offer a novel strategy to combat metastatic lung cancer.
- Further research into KDM6B and PADI4 inhibitors could lead to new treatments for advanced NSCLC.
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