Up-regulation of HO-1 promotes resistance of B-cell acute lymphocytic leukemia cells to HDAC4/5 inhibitor LMK-235 via the Smad7 pathway

Purpose: HDAC4/5 and Smad7 are potential therapeutic targets for the onset and progression of B-cell acute lymphocytic leukemia (B-ALL) and indices for clinical prognosis. In contrast, HO-1 (heat shock protein 32) plays a key role in protecting tumor cells from Apoptosis.

Methods: HDAC4/5, HO-1 and Smad7 expressions in 34 newly diagnosed B-ALL cases were detected by Real-Time PCR and Western blot. Lentivirus and small interference RNA were used to transfect B-ALL cells. The expression of Smad7 was detected after treatment with LMK-235 or Hemin and ZnPP. Apoptosis and proliferation were evaluated by flow cytometry, CCK-8 assay and Western blot.

Results: HDAC4/5 was overexpressed in B-ALL patients with high HO-1 levels. Increasing the concentration of HDAC4/5 inhibitor LMK-235 induced the decrease of Smad7 and HO-1 expressions and the Apoptosis of B-ALL cells by suppressing the phosphorylation of Akt (Protein kinase B). Up-regulating HO-1 alleviated the decrease of Smad7 expression and enhanced B-ALL resistance to LMK-235 by activating p-AKT which reduced the Apoptosis of B-ALL cells and influenced the survival of leukemia patients. Silencing Smad7 also augmented the Apoptosis rate of B-ALL cells by suppressing p-AKT.

Conclusion: HO-1 played a key role in protecting tumor cells from Apoptosis, and HDAC4/5 were related with the Apoptosis of B-ALL cells. LMK-235 may be able to improve the poor survival of leukemia patients.