Targeted Therapies in Oncohematology and Osteoncology, Department of Diagnostic Clinical and Public Health Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy.
Int J Mol Sci. 2018 Aug 9;19(8):2337. doi: 10.3390/ijms19082337.
Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.
组蛋白去乙酰化酶（HDACs）是染色质重塑的主要调控因子，作为基因表达的表观遗传调控因子。在过去的十年中，HDAC 的抑制已成为与癌症发展相关的特定表观遗传修饰的靶点。在几种血液恶性肿瘤中观察到 HDAC 的过表达。因此，观察到 HDAC 可能在各种血液恶性肿瘤中发挥作用，促使开发 HDAC 抑制剂作为潜在的抗肿瘤药物。最近，IIb 类 HDAC6 已成为一种潜在的选择性 HDACi。这种同工酶代表了一个重要的药理学靶标，用于选择性抑制。其选择性可能会降低与 pan-HDAC 抑制剂脱靶效应相关的毒性。HDAC6 也在癌症中进行了研究，特别是因为它能够协调对癌症发病机制很重要的各种细胞过程。据报道，HDAC6 在淋巴细胞中过表达，其抑制在淋巴增生性疾病的临床前和临床研究中表现出活性。HDAC6 抑制剂单独和与其他药物联合使用的各种研究为评估这些新药物在血液恶性肿瘤的临床环境中的提供了强有力的科学依据。在这篇综述中，我们描述了 HDACs、它们的抑制剂以及 HDAC6 抑制剂的最新进展，包括它们的作用机制和在淋巴增生性疾病中的作用。
