HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis
Abstract Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06467-2 |
| _version_ | 1797273067516329984 |
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| author | Jing-Yu Yang Xin-Yuan Lei Kai-Yue He Jin-Rong Guo Meng-Jie Liu Jun-Qi Li Qiu-Tong Li Zhi-Hao Jiang Lei Zhang Dan-Hui Wu Yu-Jia Li Qian-Hui Sun Yong-Ping Jian Zhi-Xiang Xu |
| author_facet | Jing-Yu Yang Xin-Yuan Lei Kai-Yue He Jin-Rong Guo Meng-Jie Liu Jun-Qi Li Qiu-Tong Li Zhi-Hao Jiang Lei Zhang Dan-Hui Wu Yu-Jia Li Qian-Hui Sun Yong-Ping Jian Zhi-Xiang Xu |
| author_sort | Jing-Yu Yang |
| collection | DOAJ |
| description | Abstract Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy. |
| first_indexed | 2024-03-07T14:38:16Z |
| format | Article |
| id | doaj.art-d9895485b3a64bd58022048ca442b56f |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:38:16Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d9895485b3a64bd58022048ca442b56f2024-03-05T20:31:21ZengNature Publishing GroupCell Death and Disease2041-48892024-02-0115211610.1038/s41419-024-06467-2HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosisJing-Yu Yang0Xin-Yuan Lei1Kai-Yue He2Jin-Rong Guo3Meng-Jie Liu4Jun-Qi Li5Qiu-Tong Li6Zhi-Hao Jiang7Lei Zhang8Dan-Hui Wu9Yu-Jia Li10Qian-Hui Sun11Yong-Ping Jian12Zhi-Xiang Xu13School of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversitySchool of Life Sciences, Henan UniversityAbstract Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.https://doi.org/10.1038/s41419-024-06467-2 |
| spellingShingle | Jing-Yu Yang Xin-Yuan Lei Kai-Yue He Jin-Rong Guo Meng-Jie Liu Jun-Qi Li Qiu-Tong Li Zhi-Hao Jiang Lei Zhang Dan-Hui Wu Yu-Jia Li Qian-Hui Sun Yong-Ping Jian Zhi-Xiang Xu HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis Cell Death and Disease |
| title | HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis |
| title_full | HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis |
| title_fullStr | HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis |
| title_full_unstemmed | HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis |
| title_short | HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis |
| title_sort | hmga1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis |
| url | https://doi.org/10.1038/s41419-024-06467-2 |
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