Histone deacetylase inhibitor LMK-235-mediated HO-1 expression induces apoptosis in multiple myeloma cells via the JNK/AP-1 signaling pathway.

Abstract:

AIMS:Histone deacetylase inhibitors (HDACis) are promising anticancer drugs that open new areas of epigenetic drug discovery. Multiple myeloma (MM) is a malignant tumor of the blood system that is difficult to cure and often relapses. Here, we investigated the in vitro effects of a novel HDACi, LMK-235, on MM cells, and explored the underlying mechanisms. MAIN METHODS:Real-time PCR and western blot were used to measure the expression of HDAC4 and HO-1 in MM cells treated with LMK-235. si-RNA was used to transfect MM cells. Hemin or ZnPP was combined to regulate heme oxygenase-1 (HO-1), and a pathway inhibitor was added to measure changes in the JNK/AP-1 signaling pathway. Apoptosis and proliferation were assessed by flow cytometry and CCK-8 assay, respectively. KEY FINDINGS:We found that LMK-235, a selective inhibitor of class IIA HDAC4/5, induced apoptosis of MM cells by downregulating HO-1 that is closely related to HDAC4. LMK-235 increased phosphorylation of JNK and c -Jun in MM cells. Downregulation of HO-1 expression in combination with LMK-235 expression further activated phosphorylation of JNK and c-Jun and induced apoptosis in MM cells. When the JNK inhibitor SP600125 was used in combination, the apoptosis phenomenon was reversed. However, when HO-1 was upregulated, LMK-235-mediated phosphorylation of JNK and c-Jun was inhibited, and apoptosis of MM cells began to decrease. SIGNIFICANCE:These data suggest that LMK-235 has potent anti-myeloma activity through regulation of HO-1-induced apoptosis via the JNK/AP-1 pathway. This provides a new concept for the treatment of multiple myeloma.

journal_name

Life Sci

journal_title

Life sciences

authors

Li X,Guo Y,Kuang X,Zhao L,Li H,Cheng B,Wang W,Zhang Z,Liu P,Wang J

doi

10.1016/j.lfs.2019.03.011

subject

Has Abstract

pub_date

2019-04-15 00:00:00

pages

146-157

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(19)30169-9

journal_volume

223

pub_type

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