HDAC6 inhibitor ACY-738 induces apoptosis and autophagy in diffuse large B-cell lymphoma cells through P53 acetylation
10.3760/cma.j.cn121090-20240826-00324
- VernacularTitle:HDAC6抑制剂ACY-738通过乙酰化P53诱导弥漫大B细胞淋巴瘤细胞凋亡和自噬
- Author:
Peijie JIANG
1
;
Jinyi LIU
;
Guancui YANG
;
Jiarun LI
;
Xiaolong TIAN
;
Shijie YANG
;
Jin WEI
;
Xi ZHANG
Author Information
1. 川北医学院附属医院血液内科，南充 637000
- Publication Type:Journal Article
- Keywords:
HDAC6;
Lymphoma, large B-cell, diffuse;
Apoptosis;
Autophagy
- From:
Chinese Journal of Hematology
2025;46(5):437-444
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the anti-tumor effect of the Histone Deacetylase 6 (HDAC6) inhibitor ACY-738 and its underlying mechanisms in Diffuse Large B-cell Lymphoma (DLBCL) .Methods:The expression of HDAC6 in various tumors and DLBCL was analyzed using bioinformatics. DLBCL cells were treated with different concentrations of ACY-738. Cell viability, DNA synthesis, and clone formation were assessed by CCK-8 assay, EdU assay, and soft agar assay, respectively. Intracellular reactive oxygen species (ROS) levels were detected by fluorescence microscopy. Morphological changes in cells were observed using transmission electron microscopy (TEM). Mitochondrial ROS levels and apoptosis were measured by flow cytometry. The expression levels of apoptosis-related and autophagy-related proteins were detected by Western blotting.Results:HDAC6 was highly expressed in DLBCL ( P<0.05). ACY-738 inhibited the proliferation, DNA synthesis, and colony formation of DLBCL cells in a dose-dependent manner ( P<0.05). Treatment with ACY-738 increased intracellular and mitochondrial ROS levels in DLBCL cells in a dose-dependent manner ( P<0.05). TEM revealed that after ACY-738 treatment, mitochondria in cells were swollen and ruptured, mitochondrial cristae were reduced or absent, autolysosomes appeared, and features characteristic of apoptosis were observed. Western blotting showed that after ACY-738 treatment, the expression of the anti-apoptotic protein BCL-2 was downregulated, while the expression of Cleaved-PARP, Cleaved caspase-3, and BAX was upregulated ( P<0.05). The expression of autophagy-related proteins Atg7, Atg3, LC3B, and P62 was downregulated, and the expression of acetylated P53 protein was upregulated ( P<0.05) . Conclusion:The HDAC6 inhibitor ACY-738 induces mitochondria-dependent apoptosis and autophagy in DLBCL cells by acetylating P53, thereby inhibiting DLBCL cell proliferation.
