SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling
Abstract SNF2L encodes an ISWI chromatin remodeling factor that promotes gene transcription and is consistently elevated in cancers. Previous studies have shown that inhibiting SNF2L expression in cancer cells leads to significant growth suppression, DNA damage, and cell death. However, the underlyi...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07221-4 |
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| _version_ | 1846164807081787392 |
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| author | Jiaguan Zhang Zeshou Gao Yi Yang Zhenhao Li Binjie Wu Chunxin Fan Yuyan Zheng Ruohan Yang Fangrong Zhang Xiaohuang Lin Daoshan Zheng |
| author_facet | Jiaguan Zhang Zeshou Gao Yi Yang Zhenhao Li Binjie Wu Chunxin Fan Yuyan Zheng Ruohan Yang Fangrong Zhang Xiaohuang Lin Daoshan Zheng |
| author_sort | Jiaguan Zhang |
| collection | DOAJ |
| description | Abstract SNF2L encodes an ISWI chromatin remodeling factor that promotes gene transcription and is consistently elevated in cancers. Previous studies have shown that inhibiting SNF2L expression in cancer cells leads to significant growth suppression, DNA damage, and cell death. However, the underlying mechanisms remain poorly understood. In this study, we demonstrated that cancer cells lacking SNF2L show significantly decreased glutathione (GSH) levels, leading to elevated reactive oxygen species (ROS) and increased oxidative stress. SNF2L deficiency also heightened the sensitivity of cancer cells to APR-246, a drug that depletes GSH and induces oxidative stress, consequently decreasing cell viability and increasing ROS levels, regardless of p53 status. Mechanistically, we found that NRF2 recruits SNF2L to the SLC7A11 promoter, leading to increased chromatin accessibility and facilitating SLC7A11 transcription. This results in decreased cystine uptake and impaired GSH biosynthesis. These findings suggest that targeting the SNF2L/SLC7A11 axis could enhance the effectiveness of APR-246 by depleting GSH and increasing ROS level in cancer cells, highlighting SNF2L as a promising therapeutic target. |
| format | Article |
| id | doaj-art-0dab2deaf1eb4730b60f9d642385b52c |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0dab2deaf1eb4730b60f9d642385b52c2024-11-17T12:51:04ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111310.1038/s41419-024-07221-4SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodelingJiaguan Zhang0Zeshou Gao1Yi Yang2Zhenhao Li3Binjie Wu4Chunxin Fan5Yuyan Zheng6Ruohan Yang7Fangrong Zhang8Xiaohuang Lin9Daoshan Zheng10Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityDepartment of Urology, The Affiliated People’s Hospital of Fujian University of Traditional Chinese MedicineKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityKey Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical UniversityAbstract SNF2L encodes an ISWI chromatin remodeling factor that promotes gene transcription and is consistently elevated in cancers. Previous studies have shown that inhibiting SNF2L expression in cancer cells leads to significant growth suppression, DNA damage, and cell death. However, the underlying mechanisms remain poorly understood. In this study, we demonstrated that cancer cells lacking SNF2L show significantly decreased glutathione (GSH) levels, leading to elevated reactive oxygen species (ROS) and increased oxidative stress. SNF2L deficiency also heightened the sensitivity of cancer cells to APR-246, a drug that depletes GSH and induces oxidative stress, consequently decreasing cell viability and increasing ROS levels, regardless of p53 status. Mechanistically, we found that NRF2 recruits SNF2L to the SLC7A11 promoter, leading to increased chromatin accessibility and facilitating SLC7A11 transcription. This results in decreased cystine uptake and impaired GSH biosynthesis. These findings suggest that targeting the SNF2L/SLC7A11 axis could enhance the effectiveness of APR-246 by depleting GSH and increasing ROS level in cancer cells, highlighting SNF2L as a promising therapeutic target.https://doi.org/10.1038/s41419-024-07221-4 |
| spellingShingle | Jiaguan Zhang Zeshou Gao Yi Yang Zhenhao Li Binjie Wu Chunxin Fan Yuyan Zheng Ruohan Yang Fangrong Zhang Xiaohuang Lin Daoshan Zheng SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling Cell Death and Disease |
| title | SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling |
| title_full | SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling |
| title_fullStr | SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling |
| title_full_unstemmed | SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling |
| title_short | SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling |
| title_sort | snf2l maintains glutathione homeostasis by initiating slc7a11 transcription through chromatin remodeling |
| url | https://doi.org/10.1038/s41419-024-07221-4 |
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