Abstract |
Histone deacetylase inhibitors (HDACis) are promising agents for the treatment of acute T lymphoblastic leukemia ( T-ALL). However, the underlying mechanisms remain to be elucidated. Based on a recent study showing that HDACis were able to modulate WNT/β- catenin signaling, we further investigated the influence of HDACis on WNT/β- catenin signaling in T-ALL cells and modulation of WNT/β- catenin signaling in mediating anti-leukemic effects of HDACis. Results from Western blotting, immunocytochemistry and a luciferase reporter assay consistently suggested that two HDACis, valproic acid (VPA) and suberoyl bishydroxamic acid (SBHA), augmented WNT/β- catenin signaling in T-ALL cells. Meanwhile, VPA and SBHA dramatically inhibited cell growth, blocked G2/M cell cycle progression and increased p21(WAF1) expression. In addition, the levels of cleaved caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP) were elevated, indicating induction of apoptosis. Furthermore, flow cytometry and Western blot for cleaved PARP showed that targeting β- catenin with shRNA attenuated the apoptosis induced by VPA and SBHA. These data demonstrate that HDACis exert profound anti-leukemic effects partly by augmentation of WNT/β- catenin signaling. Using HDACis to modulate WNT/β- catenin signaling could be an attractive new strategy for the treatment of T-ALL.
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Authors | Na Shao, Jie Zou, Jie Li, Feng Chen, Jianjian Dai, Xun Qu, Xiulian Sun, Daoxin Ma, Chunyan Ji |
Journal | Leukemia & lymphoma
(Leuk Lymphoma)
Vol. 53
Issue 9
Pg. 1769-78
(Sep 2012)
ISSN: 1029-2403 [Electronic] United States |
PMID | 22303878
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CDKN1A protein, human
- Cyclin-Dependent Kinase Inhibitor p21
- Histone Deacetylase Inhibitors
- Hydroxamic Acids
- Wnt Proteins
- beta Catenin
- suberoyl bis-hydroxamic acid
- Valproic Acid
- Poly(ADP-ribose) Polymerases
- Caspase 3
- Caspase 9
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Topics |
- Apoptosis
(drug effects)
- Blotting, Western
- Caspase 3
(metabolism)
- Caspase 9
(metabolism)
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cyclin-Dependent Kinase Inhibitor p21
(metabolism)
- Flow Cytometry
- Gene Expression Regulation, Leukemic
(genetics)
- Histone Deacetylase Inhibitors
(pharmacology)
- Humans
- Hydroxamic Acids
(pharmacology)
- Immunohistochemistry
- Jurkat Cells
- Poly(ADP-ribose) Polymerases
(metabolism)
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
(genetics, metabolism, pathology)
- RNA Interference
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
(drug effects, genetics)
- Valproic Acid
(pharmacology)
- Wnt Proteins
(metabolism)
- beta Catenin
(genetics, metabolism)
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