title: Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies.
abstract: Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maru
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000201:enzymology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology
chemical_list: D056572:Histone Deacetylase Inhibitors; D019703:Calcineurin; C525673:PPP3CA protein, human
keywords: Hematological malignancy; T-cell lymphoma; histone deacetylase inhibitor; multiple myeloma; panobinostat