PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia
Lixin Zhou
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
Search for more papers by this authorXiaoqing Jia
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorYingying Shang
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorYanni Sun
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorZhilong Liu
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorJifeng Liu
Department of Anus-Intestines, The People's Hospital of Luzhou, Luzhou, China
Search for more papers by this authorWen Jiang
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorSiyuan Deng
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorCorresponding Author
Qi Yao
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence Qi Yao, Jieping Chen and Hui Li, Department of Hematology, SW Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan St, Chongqing 400000, China.
Email: [email protected], [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Jieping Chen
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence Qi Yao, Jieping Chen and Hui Li, Department of Hematology, SW Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan St, Chongqing 400000, China.
Email: [email protected], [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Hui Li
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence Qi Yao, Jieping Chen and Hui Li, Department of Hematology, SW Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan St, Chongqing 400000, China.
Email: [email protected], [email protected] and [email protected]
Search for more papers by this authorLixin Zhou
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
Search for more papers by this authorXiaoqing Jia
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorYingying Shang
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorYanni Sun
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorZhilong Liu
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorJifeng Liu
Department of Anus-Intestines, The People's Hospital of Luzhou, Luzhou, China
Search for more papers by this authorWen Jiang
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorSiyuan Deng
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorCorresponding Author
Qi Yao
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence Qi Yao, Jieping Chen and Hui Li, Department of Hematology, SW Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan St, Chongqing 400000, China.
Email: [email protected], [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Jieping Chen
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence Qi Yao, Jieping Chen and Hui Li, Department of Hematology, SW Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan St, Chongqing 400000, China.
Email: [email protected], [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Hui Li
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Correspondence Qi Yao, Jieping Chen and Hui Li, Department of Hematology, SW Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan St, Chongqing 400000, China.
Email: [email protected], [email protected] and [email protected]
Search for more papers by this authorLixin Zhou and Xiaoqing Jia contributed equally to this study.
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an alarming mortality rate. The development of novel therapeutic targets or drugs for AML is urgently needed. Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation. Recently, ferroptosis has emerged as a novel method for targeting cancer, including AML. Epigenetic dysregulation is a hallmark of AML, and a growing body of evidence suggests that ferroptosis is subject to epigenetic regulation. Here, we identified protein arginine methyltransferase 1 (PRMT1) as a ferroptosis regulator in AML. The type I PRMT inhibitor GSK3368715 promoted ferroptosis sensitivity in vitro and in vivo. Moreover, PRMT1-knockout cells exhibited significantly increased sensitivity to ferroptosis, suggesting that PRMT1 is the primary target of GSK3368715 in AML. Mechanistically, both GSK3368715 and PRMT1 knockout upregulated acyl-CoA synthetase long-chain family member 1 (ACSL1), which acts as a ferroptosis promoter by increasing lipid peroxidation. Knockout ACSL1 reduced the ferroptosis sensitivity of AML cells following GSK3368715 treatment. Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome-wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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