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J. He et al.
induces STAT3 de-phosphorylation, thus reducing MM cell growth.8,9 Based on our results and findings from previous studies, we speculated that chidamide promoted MM cell apoptosis by inhibiting the JAK2/STAT3 signaling pathway. Furthermore, platelet factor 4 up-regulates SOSC3 expres- sion to induce MM cell apoptosis by inhibiting STAT3.24 The expression of SOCS3, which acts as a tumor suppres- sor gene and is always silenced by epigenetic modulation in hematological malignancies, was up-regulated in chi- damide-treated cells, which explains the decrease in p-JAK2 and p-STAT3 levels.22,25 Bcl-2 family members, including Bcl- xL and Myc, are downstream targets of the JAK2/STAT3 signaling pathway.23 Moreover, active caspase-3 is a nega- tive regulator of the Bcl-2 family which represses the expression of Bcl-xL and Mcl-1 and subsequently induces cell apoptosis.26 Chidamide inhibited the constitutive acti- vation of the JAK2/STAT3 pathway and caspase-3 activa- tion, thus down-regulating Bcl-xL and Myc.
Myeloma-associated bone disease is a major complica- tion of MM and decreases patients’ quality of life.2,27 Interactions between myeloma cells and OCs not only support myeloma survival but also increase osteoclasto- genesis and inhibit osteoblastogenesis, leading to oste- olytic bone lesions and myeloma progression.28,29 An important finding of our study is that chidamide not only suppresses the formation and function of OCs in vitro, but also prevents myeloma-associated bone disease in vivo. Bone remodeling is a balance between bone resorp- tion and bone formation.30 Active OCs, together with myeloma cells, increase bone resorption and inhibit osteoblast differentiation, leading to myeloma-associat- ed bone disease. Chidamide-induced myeloma cell apop- tosis prevented osteoclast maturation and showed no inhibitory effect on osteoblast differentiation. HDACs, which are targets of chidamide, are involved in OC for- mation.10,11,31 HDAC2 is reported to play an important role in OC maturation by activating the AKT pathway.11 Additionally, HDAC3 knockdown decreases the expres- sion of NFATc1, Cathepsin K and DC-STAMP, thus inhibiting OC formation.31 Based on our data, chidamide repressed the expression of key factors, such as NFATc1, c-fos and Cathepsin K, during OC maturation, suggest-
ing that chidamide suppresses OC differentiation by inhibiting the function of its targets (such as HDAC2 and HDAC3). A previous study reported the effect of HDAC10 on osteoclast differentiation. They showed that during OC differentiation, HDAC10 levels gradually increased, which is consistent with our study. However, when they knocked down HDAC10 in monocytes, OC differentiation was promoted, indicating that HDAC10 may have a negative effect on OC differentiation.32 However, in our study, following chidamide treatment and inhibition of OC formation, HDAC10 was down- regulated at the protein level. Since chidamide can inhib- it other HDACs in addition to HDAC10, its inhibitory effect on OC differentiation may not have been caused by HDAC10 down-regulation. Both MM cells and OCs can suppress the differentiation of osteoblasts. As a pre- vious study reported, OCs inhibited osteoblast differen- tiation though exosomes containing micro ribonucleic acids (miRNAs) and some cytokines.33 In our study, chi- damide could induce MM cell apoptosis and abrupt OCs maturation, indicating that chidamide may attenuate the inhibitory effect of MM cells and OCs on osteoblasts. When BMSCs were treated with chidamide during osteoblast differentiation, chidamide increased the gene expression levels of ALP and OCN while reducing the gene expression level of Activin A, which acted as a nega- tive regulator in osteoblast differentiation via SMAD2- mediated DLX5 down-regulation.34 The ARS experiment showed neither promotion nor an inhibitory effect on osteoblast differentiation. These results may explain the direct bone-protective effect of chidamide in the mouse models.
Our work reveals the dual anti-myeloma and bone-pro- tective effects of chidamide in vitro and in vivo. These find- ings strongly support the potential clinical use of this drug as a treatment for MM in the near future.
Funding
This work was supported by the Funds for the National Natural Science Foundation of China (Grant No. 91742110 and 81471532) and the Funds for the Natural Science Foundation of Zhejiang province, China (LY17H080001).
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