Hyper-activation of WNT/β-catenin signaling pathway mediates anti-tumor effects of histone deacetylase inhibitors in acute T lymphoblastic leukemia.
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.
Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, P R China.
Na
N
Shao
Jie
J
Zou
Jie
J
Li
Feng
F
Chen
Jianjian
J
Dai
Xun
X
Qu
Xiulian
X
Sun
Daoxin
D
Ma
Chunyan
C
Ji
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D019169:Jurkat Cells; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051153:Wnt Proteins; D051176:beta Catenin; C528828:suberoyl bis-hydroxamic acid; D014635:Valproic Acid; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9