イマイ　ヨウイチ   Imai Youichi   今井　陽一    所属   医学部 医学科（東京女子医科大学病院）    職種   非常勤講師
論文種別	総説
言語種別	英語
査読の有無	査読あり
表題	Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies.
掲載誌名	正式名：Cancer science 略　 称：Cancer Sci ISSNコード：(1349-7006)1347-9032(Linking)
掲載区分	国外
巻・号・頁	107(11),pp.1543-1549
著者・共著者	IMAI Yoichi†*, MARU Yoshiro, TANAKA Junji
担当区分	筆頭著者,責任著者
発行年月	2016/11
概要	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.
DOI	10.1111/cas.13062
PMID	27554046