HDAC Inhibitors Exert Anti-Myeloma Effects through Multiple Modes of Action

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.

Inhibitors of HSP90 in melanoma

“…Transcriptional regulation of HSP90 expression is mainly controlled by HSFs (heat shock factors), which bind to HSE (heat shock element) located in the promoter region of HSP90 [31,32]. HDAC6 (histone deacetylase 6)-mediated regulation of HSP90 stability, posttranslational modifications of cytosolic HSP90 that include phosphorylation, acetylation, methylation, ubiquitylation and S-nitrosylation have been extensively discussed elsewhere [30,[33][34][35].…”

Anti-Cancer Effects of CKD-581, a Potent Histone Deacetylase Inhibitor against Diffuse Large B-Cell Lymphoma

“…For instance, bortezomib could be suitable for combination with CKD-581. It has also been reported that HDAC inhibitors enhance the accumulation of misfolded proteins induced by proteasome inhibitors [40,41]. Bruton's tyrosine kinase (BTK) inhibitor has also been proposed as a combination therapy to HDAC inhibitor treatment, to overcome acquired resistance in lymphoma [42].…”

Histone Deacetylase 6 as a Therapeutic Target in B cell-associated Hematological Malignancies

“…HDAC6 may regulate the expression of PD-L1 through the transcription factor STAT3, but the molecular mechanism of how HDAC6 regulates PD-1 is still unclear (Lienlaf et al, 2016). In addition, ACY-241 can enhance anti-MM tumor immune activity by increasing the expression of surface antigens B7 and MHC on dendritic cells and MM cells, promoting the proliferation of CD4 + /CD8 + T cells and reducing the number of MM cells, regulatory T cells, and myeloid-derived suppressor cells (Bae et al, 2018;Imai et al, 2019).…”

“…HDAC6 plays an important role in this process by binding to polyubiquitinated proteins and recruiting protein cargoes to dynein, which are then transported along microtubules to aggregates ( Mishima et al., 2015 ; Huang et al., 2019 ). The HDAC6 inhibitors ricolinostat and WT161 inhibited protein aggregate formation in vivo , and combined use with proteasome inhibitors further resulted in excessive accumulation of misfolded/unfolded proteins, ER stress, and caspase-dependent apoptosis ( Santo et al., 2012 ; Hideshima et al., 2016 ; Vogl et al., 2017 ; Imai et al., 2019 ) ( Figure 1C ).…”