Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

Histone deacetylases ( HDAC s) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDAC s, especially involving non‐histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDAC s potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML 1‐ ETO , which mediates transcriptional repression through its interaction with a complex including HDAC 1. Recurrent mutations in epigenetic regulators are found in T‐cell lymphomas ( TCL s), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCL s. 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 ( PPP 3 CA ), 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 HDAC 6 inhibition. Aberrant PPP 3 CA expression in advanced MM indicated a possible correlation between high PPP 3 CA expression and the pathogenesis of MM . Furthermore, PPP 3 CA was suggested as a common target of panobinostat and bortezomib.