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.

Keywords::

• HDACis
• WNT/b-catenin signaling
• T-ALL
• apoptosis
• cell cycle

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (30871088, 81070407, 81000223), the “Eleventh Five-Year” National Science and Technology Support Program of China, SRFDP of the Educational Ministry (20100131110060), the Shandong Technological Development Project (2009GG20002020, 2008GJHZ10202, 2008BS03001, 2009HD012, BS2009SW014, 2007BS03049, 2010GSF10235) and the Independent Innovation Fund of Shandong University, IIFSDU (yzc10071).

Potential conflict of interest

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