Hyper-activation of WNT/β-catenin signaling pathway mediates anti-tumor effects of histone deacetylase inhibitors in acute T lymphoblastic leukemia.

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.

• 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)

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

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)