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

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.