Biomolecules & Therapeutics

  • 제33권1호
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  • Pages.182-192
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  • 2025
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Epigenetic Regulation of Nuclear Factor Erythroid-2-Related Factor 2 in Colorectal Cancer Cells Resistant to Ionizing Radiation

  • Kyoung Ah Kang (Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University) ;
  • Jinny Park (Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine) ;
  • Mei Jing Piao (Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University) ;
  • Pincha Devage Sameera Madushan Fernando (Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University) ;
  • Herath Mudiyanselage Udari Lakmini Herath (Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University) ;
  • Herath Mudiyanselage Maheshika Madhuwanthi Senavirathna (Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University) ;
  • Jung-Hwan Kim (Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University) ;
  • Suk Ju Cho (Department of Anesthesiology, Jeju National University Hospital, College of Medicine, Jeju National University) ;
  • Jin Won Hyun (Department of Biochemistry, College of Medicine, and Jeju Natural Medicine Research Center, Jeju National University)
  • 투고 : 2024.10.04
  • 심사 : 2024.12.12
  • 발행 : 2025.01.01
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초록

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.

키워드

과제정보

This work was supported by a research grant from the Jeju National University Hospital in 2023.

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