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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. [ABSTRACT FROM AUTHOR]

Inhibition of histone deacetylase (HDAC) is a promising therapeutic strategy for various hematologic cancers. Panobinostat has been approved for treating patients with multiple myeloma (MM) by the FDA. Since the mechanism for the resistance of panobinostat to MM remains elusive, we aimed to clarify this mechanism and the synergism of panobinostat with lenalidomide. The mRNA and protein of transcription factor IRF4 were overexpressed in CD138 + mononuclear cells from MM patients compared with in those from healthy donors. Given that direct IRF4 inhibitors are clinically unavailable, we intended to explore the mechanism by which IRF4 expression was regulated in MM. Heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors, and its expression is positively correlated with IRF4 mRNA and protein expression levels. Herein, panobinostat induced acetylation of histone H3K9 and activation of caspase-3 in MM cells, being inversely correlated with the reduction of HO-1/IRF4/MYC protein levels. Adding Z-DEVD-FMK, a caspase-3 inhibitor, abolished the HO-1/IRF4 reduction by panobinostat alone or in combination with lenalidomide, suggesting that caspase-3-mediated HO-1/IRF4/MYC degradation occurred. Given that lenalidomide stabilized cereblon and facilitated IRF4 degradation in MM cells, we combined it with LBH589, an HDAC inhibitor. LBH589 and lenalidomide exerted synergistic effects, and LBH589 reversed the efficacy of lenalidomide on the resistance of CD138 + primary MM cells, in part due to simultaneous suppression of HO-1, IRF4 and MYC. The results provide an eligible therapeutic strategy for targeting MM depending on the IRF4 network and clinical testing of this drug combination in MM patients. [ABSTRACT FROM AUTHOR]