Chidamide triggers pyroptosis in T-cell lymphoblastic lymphoma/leukemia via the FOXO1/GSDME axis.
10.1097/CM9.0000000000003214
- Author:
Xinlei LI
1
;
Bangdong LIU
1
;
Dezhi HUANG
1
;
Naya MA
1
;
Jing XIA
1
;
Xianlan ZHAO
1
;
Yishuo DUAN
1
;
Fu LI
1
;
Shijia LIN
1
;
Shuhan TANG
1
;
Qiong LI
1
;
Jun RAO
1
;
Xi ZHANG
1
Author Information
1. Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
- Publication Type:Journal Article
- Keywords:
Forkhead box O1;
Gasdermin E;
Histone deacetylase inhibitor;
Pyroptosis;
T-cell lymphoblastic lymphoma/leukemia
- MeSH:
Humans;
Pyroptosis/drug effects*;
Forkhead Box Protein O1/genetics*;
Aminopyridines/pharmacology*;
Animals;
Mice;
Benzamides/pharmacology*;
Cell Line, Tumor;
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*;
Phosphate-Binding Proteins/metabolism*;
Histone Deacetylase Inhibitors/pharmacology*;
Jurkat Cells;
Histone Deacetylases/metabolism*;
Apoptosis/drug effects*;
Gasdermins
- From:
Chinese Medical Journal
2025;138(10):1213-1224
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL.
METHODS:HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse.
RESULTS:The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo .
CONCLUSIONS:This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
