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Cancers 2019, 11(4), 475; https://doi.org/10.3390/cancers11040475

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

1
Department of Hematology/Oncology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
2
Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
*
Author to whom correspondence should be addressed.
Received: 25 January 2019 / Revised: 20 March 2019 / Accepted: 25 March 2019 / Published: 4 April 2019
(This article belongs to the Collection Histone Modification in Cancer)
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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. View Full-Text
Keywords: HDAC inhibitor; histone modification; multiple myeloma; panobinostat; HDAC6; HSP90 HDAC inhibitor; histone modification; multiple myeloma; panobinostat; HDAC6; HSP90
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Imai, Y.; Hirano, M.; Kobayashi, M.; Futami, M.; Tojo, A. HDAC Inhibitors Exert Anti-Myeloma Effects through Multiple Modes of Action. Cancers 2019, 11, 475.

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