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

Abstract

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.

• Authors: Yongling Guo, Qin Fang, Dan Ma, Kunling Yu, Bingqing Cheng, Sishi Tang, Tingting Lu, Weili Wang, Jishi Wang
• Journal: Life sciences (Life Sci) Vol. 207 Pg. 386-394 (Aug 15 2018) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 29886060 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• RNA, Small Interfering
• Repressor Proteins
• SMAD7 protein, human
• Smad7 Protein
• HMOX1 protein, human
• Heme Oxygenase-1
• HDAC4 protein, human
• HDAC5 protein, human
• Histone Deacetylases

Topics

• Adolescent
• Adult
• Aged
• Apoptosis
• Benzamides (pharmacology)
• Cell Line, Tumor
• Cell Survival
• Child
• Disease Progression
• Female
• Gene Expression Regulation, Leukemic
• Gene Silencing
• Heme Oxygenase-1 (metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases
• Humans
• Leukemia, B-Cell (metabolism)
• Male
• Middle Aged
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism)
• Prognosis
• RNA, Small Interfering (metabolism)
• Repressor Proteins (antagonists & inhibitors)
• Smad7 Protein (metabolism)
• Treatment Outcome
• Up-Regulation
• Young Adult