Abstract
HDACs are critical regulators of gene expression that function through histone modification. Non-histone proteins and histones are targeted by these proteins and the inhibition of HDACs results in various biological effects. Moreover, the aberrant expression and function of these proteins is thought to be related to the pathogenesis of multiple myeloma (MM) and several inhibitors have been introduced or clinically tested. Panobinostat, a pan-HDAC inhibitor, in combination with a proteasome inhibitor and dexamethasone has improved survival in relapsing/refractory MM patients. We revealed that panobinostat inhibits MM cell growth by degrading the protein PPP3CA, a catalytic subunit of calcineurin. This degradation was suggested to be mediated by suppression of the chaperone function of HSP90 due to HDAC6 inhibition. Cytotoxicity due to the epigenetic regulation of tumor-associated genes by HDAC inhibitors has also been reported. In addition, HDAC6 inhibition enhances tumor immunity and has been suggested to strengthen the cytotoxic effects of therapeutic antibodies against myeloma. Furthermore, therapeutic strategies to enhance the anti-myeloma effects of HDAC inhibitors through the addition of other agents has been intensely evaluated. Thus, the treatment of patients with MM using HDAC inhibitors is promising as these drugs exert their effects through multiple modes of action.
Highlights
Multiple myeloma (MM) is a B-cell malignancy that can be difficult to treat
There was a significant increase in the expression of HDAC3 in myeloma cells when compared to that in normal plasma cells. These results indicate that the overexpression of class I HDACs, and HDAC1, is associated with poor prognosis in MM
Vorinostat, a class I/II HDAC inhibitor, was shown to modify the acetylation and methylation of core histones and tightly restrict enzyme accessibility at the p21WAF1 promoter region of myeloma cells [15]. This epigenetic modulation was suggested to induce the expression of p21WAF1, a target of proteasome inhibition that is stabilized by bortezomib, and its induction is related to apoptosis in myeloma cells [16]
Summary
Multiple myeloma (MM) is a B-cell malignancy that can be difficult to treat. The introduction of autologous stem cell transplantation and other novel drugs including a proteasome inhibitor (bortezomib) and IMiDs (thalidomide, lenalidomide, and pomalidomide), has improved the survival rates of patients with MM, many patients with relapsing/refractory MM remain and new therapies to treat such individuals are needed. In MM, progression-free survival was significantly shorter in myeloma patients with higher levels of class I HDAC expression [1]. For this reason, HDACs have been proposed to be good candidates for the targeted treatment of MM. Class I HDACs (1, 2, 3, and 8) are generally located in the nucleus where they regulate gene expression through the deacetylation of histones These have been suggested to function as epigenetic regulators through histone modifications. We describe the clinical use and mechanisms of action, including epigenetic, protein stabilizing, and immunogenic, of HDAC inhibitors with respect to the treatment of MM
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