Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan.
COMSATS Institute of Information Technology, Islamabad, Pakistan.
Arch Immunol Ther Exp (Warsz). 2018 Feb;66(1):31-44. doi: 10.1007/s00005-017-0488-0. Epub 2017 Aug 30.
In the past few years, basic and clinical scientists have witnessed landmark achievements in many research projects, such as those conducted by the US National Institutes of Health Roadmap Epigenomics Mapping Consortium, the International Human Epigenome Consortium, The Cancer Genome Atlas Network and the International Cancer Genome Consortium, which have provided near-complete resolution of epigenetic landscape in different diseases. Furthermore, genome sequencing of tumors has provided compelling evidence related to frequent existence of mutations in readers, erasers and writers of epigenome in different cancers. Histone acetylation is an intricate mechanism modulated by two opposing sets of enzymes and deeply studied as a key biological phenomenon in 1964 by Vincent Allfrey and colleagues. The research group suggested that this protein modification contributed substantially in transcriptional regulation. Subsequently, histone deacetylases (HDACs), histone acetyltransferases and acetyl-Lys-binding proteins were identified as transcriptional mediators, which further deepened our comprehension regarding biochemical modifications. Overwhelmingly increasing high-impact research is improving our understanding of this molecularly controlled mechanism; moreover, quantification and identification of lysine acetylation by mass spectrometry has added new layers of information. We partition this multi-component review into how both activity and expression of HDAC are targeted using natural agents. We also set spotlight on how oncogenic fusion proteins tactfully utilize HDAC-associated nano-machinery to modulate expression of different genes and how HDAC inhibitors regulate TRAIL-induced apoptosis in cancer cells. HDAC inhibitors have been reported to upregulate expression of TRAIL receptors and protect TRAIL from proteasomal degradation. Deeper understanding of HDAC biology will be useful for stratification and selection of patients who are responders, non-responders and poor-responders for HDACi therapy, and for the rational design of combination studies using HDACi.
在过去的几年中，基础和临床科学家见证了许多研究项目的里程碑式成就，例如美国国立卫生研究院路线图表观基因组学图谱联盟、国际人类表观基因组联盟、癌症基因组图谱网络和国际癌症基因组联盟等机构的研究项目，这些项目提供了不同疾病中表观基因组的近乎完整解析。此外，肿瘤的基因组测序为不同癌症中表观基因组的读取器、擦除器和写入器经常存在突变提供了令人信服的证据。组蛋白乙酰化是一种由两组相互对立的酶调节的复杂机制，于 1964 年由 Vincent Allfrey 及其同事作为一个关键的生物学现象进行了深入研究。该研究小组认为，这种蛋白质修饰对转录调控有很大的贡献。随后，组蛋白去乙酰化酶（HDACs）、组蛋白乙酰转移酶和乙酰化赖氨酸结合蛋白被确定为转录调节剂，这进一步加深了我们对生化修饰的理解。越来越多的高影响力研究正在提高我们对这种分子控制机制的理解；此外，通过质谱法对赖氨酸乙酰化的定量和鉴定增加了新的信息层。我们将这个多组分综述分为如何使用天然剂靶向 HDAC 的活性和表达。我们还重点介绍了致癌融合蛋白如何巧妙地利用与 HDAC 相关的纳米机器来调节不同基因的表达，以及 HDAC 抑制剂如何调节 TRAIL 诱导的癌细胞凋亡。据报道，HDAC 抑制剂可上调 TRAIL 受体的表达并保护 TRAIL 免受蛋白酶体降解。对 HDAC 生物学的更深入理解将有助于分层和选择对 HDACi 治疗有反应、无反应和反应不佳的患者，并为使用 HDACi 的联合研究进行合理设计。
