USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1
Abstract Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. Howeve...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05915-9 |
| _version_ | 1797784342850699264 |
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| author | Junyi Duan Daoyuan Huang Cheng Liu Yangbo Lv Lei Zhang Fen Chang Xiangyu Zeng Li Li Weiping Wang Genze Shao |
| author_facet | Junyi Duan Daoyuan Huang Cheng Liu Yangbo Lv Lei Zhang Fen Chang Xiangyu Zeng Li Li Weiping Wang Genze Shao |
| author_sort | Junyi Duan |
| collection | DOAJ |
| description | Abstract Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment. |
| first_indexed | 2024-03-13T00:39:26Z |
| format | Article |
| id | doaj.art-2b925fb1cd0e4d19a980de5c6c7fd7f7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T00:39:26Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-2b925fb1cd0e4d19a980de5c6c7fd7f72023-07-09T11:26:28ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711510.1038/s41419-023-05915-9USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1Junyi Duan0Daoyuan Huang1Cheng Liu2Yangbo Lv3Lei Zhang4Fen Chang5Xiangyu Zeng6Li Li7Weiping Wang8Genze Shao9Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science CenterAdvanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical UniversityProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer InstituteColorectal Department of Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s HospitalProgram for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University International Cancer InstituteDepartment of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology (Shandong University)Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Cell Biology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, Peking University Health Science CenterDepartment of Cell Biology, School of Basic Medical Sciences, Peking University Health Science CenterAbstract Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation. Colorectal cancer (CRC) cells evade ferroptosis despite their requirement of substantial iron and reactive oxygen species (ROS) to sustain active metabolism and extensive proliferation. However, the underlying mechanism is unclear. Herein, we report the role of lymphoid-specific helicase (LSH), a chromatin-remodeling protein, in suppressing erastin-induced ferroptosis in CRC cells. We demonstrate that erastin treatment leads to dose- and time-dependent downregulation of LSH in CRC cells, and depletion of LSH increases cell sensitivity to ferroptosis. Mechanistically, LSH interacts with and is stabilized by ubiquitin-specific protease 11 (USP11) via deubiquitination; this interaction was disrupted by erastin treatment, resulting in increased ubiquitination and LSH degradation. Moreover, we identified cytochrome P450 family 24 subfamily A member 1 (CYP24A1) as a transcriptional target of LSH. LSH binds to the CYP24A1 promoter, promoting nucleosome eviction and reducing H3K27me3 occupancy, thus leading to transcription of CYP24A1. This cascade inhibits excessive intracellular Ca2+ influx, thereby reducing lipid peroxidation and ultimately conferring resistance to ferroptosis. Importantly, aberrant expression of USP11, LSH, and CYP24A1 is observed in CRC tissues and correlates with poor patient prognosis. Taken together, our study demonstrates the crucial role of the USP11/LSH/CYP24A1 signaling axis in inhibiting ferroptosis in CRC, highlighting its potential as a therapeutic target in CRC treatment.https://doi.org/10.1038/s41419-023-05915-9 |
| spellingShingle | Junyi Duan Daoyuan Huang Cheng Liu Yangbo Lv Lei Zhang Fen Chang Xiangyu Zeng Li Li Weiping Wang Genze Shao USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1 Cell Death and Disease |
| title | USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1 |
| title_full | USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1 |
| title_fullStr | USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1 |
| title_full_unstemmed | USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1 |
| title_short | USP11-mediated LSH deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of CYP24A1 |
| title_sort | usp11 mediated lsh deubiquitination inhibits ferroptosis in colorectal cancer through epigenetic activation of cyp24a1 |
| url | https://doi.org/10.1038/s41419-023-05915-9 |
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