Biomol Ther.
2025 Jan;33(1):182-192. 10.4062/biomolther.2024.183.
Epigenetic Regulation of Nuclear Factor Erythroid-2-Related Factor 2 in Colorectal Cancer Cells Resistant to Ionizing Radiation
- Affiliations
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- 1Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University, Jeju 63243, Republic of Korea
- 2Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan 15355, Republic of Korea
- 3Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea
- 4Department of Anesthesiology, Jeju National University Hospital, College of Medicine, Jeju National University, Jeju 63241, Republic of Korea
- KMID: 2563818
- DOI: http://doi.org/10.4062/biomolther.2024.183
Abstract
- γ-Radiation resistance is a major obstacle to the success of radiotherapy in colorectal cancer. Antioxidant-related factors contribute to resistance to radiation therapy and, therefore, are targets for improving the therapeutic response. In this study, we evaluated the molecular mechanisms underlying γ-radiation resistance using the colorectal cancer cell line SNUC5 and γ-radiation-resistant variant SNUC5/RR, including analyses of the role of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that regulates antioxidant enzymes, and related epigenetic regulators. Reactive oxygen species (ROS) levels, antioxidant enzyme expression, NRF2 expression, and nuclear translocation were higher in SNUC5/RR cells irradiated with or without 8 Gy than in SNUC5 cells. The DNA demethylase ten-eleven translocation 1 (TET1) expression and TET1 binding to the NRF2 promoter in SNUC5/RR cells were stronger than those in SNUC5 cells, indicating lower methylation of CpG islands in the NRF2 promoter. TET1 knockdown in SNUC5/RR cells suppressed NRF2 expression significantly. Additionally, histone mixed-lineage leukemia (MLL), a histone methyltransferase, was upregulated, leading to increased trimethylation of histone H3 lysine 4, whereas enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, was downregulated, leading to decreased trimethylation of histone H3 lysine 27. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) levels were lower and higher in SNUC5/RR cells than in SNUC5 cells, respectively. MLL and HAT knockdown in SNUC5/RR cells irradiated with or without 8 Gy decreased levels of NRF2 and heme-oxygenase 1, resulting in enhanced γ-radiation sensitivity. These findings support NRF2 as a target for improving the response to radiotherapy in patients with colorectal cancer.
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