Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression
Abstract Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial rol...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-03032-9 |
| _version_ | 1797209025959428096 |
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| author | Yaya Qiao Meng Su Huifang Zhao Huanle Liu Chenxi Wang Xintong Dai Lingling Liu Guangju Liu Huanran Sun Mingming Sun Jiyan Wang Zhen Li Jun Fan Quan Zhang Chunshen Li Fangmin Situ Jun Xue Zhenghu Jia Chunze Zhang Shuai Zhang Changliang Shan |
| author_facet | Yaya Qiao Meng Su Huifang Zhao Huanle Liu Chenxi Wang Xintong Dai Lingling Liu Guangju Liu Huanran Sun Mingming Sun Jiyan Wang Zhen Li Jun Fan Quan Zhang Chunshen Li Fangmin Situ Jun Xue Zhenghu Jia Chunze Zhang Shuai Zhang Changliang Shan |
| author_sort | Yaya Qiao |
| collection | DOAJ |
| description | Abstract Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression. |
| first_indexed | 2024-04-24T09:48:09Z |
| format | Article |
| id | doaj.art-e16df1e8d964488fb1e89a09db7e688e |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-24T09:48:09Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e16df1e8d964488fb1e89a09db7e688e2024-04-14T11:32:46ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-04-0143111810.1186/s13046-024-03032-9Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expressionYaya Qiao0Meng Su1Huifang Zhao2Huanle Liu3Chenxi Wang4Xintong Dai5Lingling Liu6Guangju Liu7Huanran Sun8Mingming Sun9Jiyan Wang10Zhen Li11Jun Fan12Quan Zhang13Chunshen Li14Fangmin Situ15Jun Xue16Zhenghu Jia17Chunze Zhang18Shuai Zhang19Changliang Shan20State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversitySchool of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical UniversitySchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityGuangzhou key laboratory for clinical rapid diagnosis and early warning of infectious diseases, KingMed School of Laboratory Medicine, Guangzhou Medical UniversityDepartment of Medical Biochemistry and Molecular Biology, School of Medicine, Guangdong Second Provincial General Hospital, Jinan UniversityState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversitySchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineCollege of Chinese and Culture, Jinan UniversityDepartment of General Surgery, The First Affiliated Hospital of Hebei North UniversityThe First Affiliated Hospital, Biomedical Translational Research Institute and Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan UniversityDepartment of Colorectal Surgery, Tianjin Union Medical Center, Nankai UniversitySchool of Integrative Medicine, Tianjin University of Traditional Chinese MedicineState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai UniversityAbstract Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.https://doi.org/10.1186/s13046-024-03032-9Colorectal cancer (CRC)N6-methyladenosine (m6A)FerroptosisFat mass and obesity-associated protein (FTO)Solute carrier family 7 member 11 (SLC7A11)Glutathione peroxidase 4 (GPX4) |
| spellingShingle | Yaya Qiao Meng Su Huifang Zhao Huanle Liu Chenxi Wang Xintong Dai Lingling Liu Guangju Liu Huanran Sun Mingming Sun Jiyan Wang Zhen Li Jun Fan Quan Zhang Chunshen Li Fangmin Situ Jun Xue Zhenghu Jia Chunze Zhang Shuai Zhang Changliang Shan Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression Journal of Experimental & Clinical Cancer Research Colorectal cancer (CRC) N6-methyladenosine (m6A) Ferroptosis Fat mass and obesity-associated protein (FTO) Solute carrier family 7 member 11 (SLC7A11) Glutathione peroxidase 4 (GPX4) |
| title | Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression |
| title_full | Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression |
| title_fullStr | Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression |
| title_full_unstemmed | Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression |
| title_short | Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression |
| title_sort | targeting fto induces colorectal cancer ferroptotic cell death by decreasing slc7a11 gpx4 expression |
| topic | Colorectal cancer (CRC) N6-methyladenosine (m6A) Ferroptosis Fat mass and obesity-associated protein (FTO) Solute carrier family 7 member 11 (SLC7A11) Glutathione peroxidase 4 (GPX4) |
| url | https://doi.org/10.1186/s13046-024-03032-9 |
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