Notch1 signaling is irresponsible to the anti-leukemic effect of HDACis in B-ALL Nalm-6 cells

Abstract

B cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy with limited treatment strategies. Histone deacetylases inhibitors (HDACis) are promising novel tools for cancer therapy, whose anti-tumor effects and the underlying mechanisms on B-ALL remain to be elucidated. Recently, Notch1 signaling activation has been reported to be involved in the anti-tumor effects of HDACis. This study was conducted to determine: the influence of two HDACis, valproic acid (VPA) and suberic bishydroxamic acid (SBHA), on Notch1 signaling as well as the role of Notch1 signaling in the anti-tumor effects of HDACis in B-ALL cells. To address this issue, we treated Nalm-6 B-ALL cell line with VPA and SBHA (HDACis), then, cell proliferation, cell cycle, apoptosis, and expression of Notch1 related genes were analyzed. We found that VPA and SBHA dramatically inhibited cell growth, induced a G1/S cell cycle block in accompany with an elevated level of P21(WAF1) protein in Nalm-6 cells. The levels of cleaved caspase-9, caspase-3, and PARP were elevated, indicating the activation of apoptosis. However, no change in the expression of Notch1 and its downstream genes were found by quantitative real-time PCR and Western blot. Our result suggested that Notch1 signaling is irresponsible for the anti-leukemic effect of HDACis in B-ALL cells. New hypotheses and future studies are needed to explore the underlying mechanisms of the anti-cancer effect in B-ALL.