Department of Biophysics, Manipal School of Life Sciences, MAHE, Manipal, India.
Department of Biotechnology, Manipal School of Life Sciences, MAHE, Manipal, India.
Pharmacol Res. 2021 Aug;170:105695. doi: 10.1016/j.phrs.2021.105695. Epub 2021 Jun 1.
Acetylation and deacetylation of histone and several non-histone proteins are the two important processes amongst the different modes of epigenetic modulation that are involved in regulating cancer initiation and development. Abnormal expression of histone deacetylases (HDACs) is often reported in various types of cancers. Few pan HDAC inhibitors have been approved for use as therapeutic interventions for cancer treatment including vorinostat, belinostat and panobinostat. However, not all the HDAC isoforms are abnormally expressed in certain cancers, such as in the case of, ovarian cancer where overexpression of HDAC1-3, lung cancer where overexpression of HDAC 1 and 3 and gastric cancer where overexpression of HDAC2 is seen. Therefore, pan-inhibition of HDAC is not an efficient way to combat cancer via HDAC inhibition. Hence, isoform-selective HDAC inhibition can be one of the best therapeutic strategies in the treatment of cancer. In this context since aberrant expression of HDAC2 largely contributes to cancer progression by silencing pro-apoptotic protein expressions such as NOXA and APAF1 (caspase 9-activating proteins) and inactivation of tumor suppressor p53, HDAC2 specific inhibitors may help to develop not only the direct targets but also indirect targets that are crucial for tumor development. However, to develop a HDAC2 specific and potent inhibitor, extensive knowledge of its structure and specific functions is essential. The present review updates details on the structural features, physiological functions, and roles of HDAC2 in different types of cancer, emphasizing the challenges and status of the development of HDAC2 selective inhibitors against various types of cancer.
组蛋白和几种非组蛋白蛋白质的乙酰化和去乙酰化是参与调节癌症发生和发展的不同表观遗传调控模式中的两个重要过程。组蛋白去乙酰化酶（HDACs）的异常表达经常在各种类型的癌症中报道。有几种泛 HDAC 抑制剂被批准用于癌症治疗的治疗干预，包括伏立诺他、贝林司他和帕比司他。然而，并非所有的 HDAC 同工型在某些癌症中都异常表达，例如在卵巢癌中 HDAC1-3 过表达，在肺癌中 HDAC1 和 3 过表达，在胃癌中 HDAC2 过表达。因此，泛 HDAC 抑制不是通过 HDAC 抑制来有效对抗癌症的方法。因此，同工型选择性 HDAC 抑制可能是癌症治疗中最佳治疗策略之一。在这种情况下，由于 HDAC2 的异常表达通过沉默促凋亡蛋白表达（如 NOXA 和 APAF1（胱天蛋白酶 9 激活蛋白））和失活肿瘤抑制因子 p53，极大地促进了癌症的进展，因此 HDAC2 特异性抑制剂可能有助于不仅开发直接靶点，还开发间接靶点，这些靶点对肿瘤发展至关重要。然而，要开发针对 HDAC2 的特异性和强效抑制剂，需要广泛了解其结构和特定功能。本综述更新了关于 HDAC2 的结构特征、生理功能和在不同类型癌症中的作用的详细信息，强调了针对各种类型癌症开发 HDAC2 选择性抑制剂的挑战和现状。
