Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, United States.
Curr Mol Pharmacol. 2019;12(3):215-229. doi: 10.2174/1874467212666190215112915.
Epigenetic alterations comprise key regulatory events that dynamically alter gene expression and their deregulation is commonly linked to the pathogenesis of various diseases, including cancer. Unlike DNA mutations, epigenetic alterations involve modifications to proteins and nucleic acids that regulate chromatin structure without affecting the underlying DNA sequence, altering the accessibility of the transcriptional machinery to the DNA, thus modulating gene expression. In cancer cells, this often involves the silencing of tumor suppressor genes or the increased expression of genes involved in oncogenesis. Advances in laboratory medicine have made it possible to map critical epigenetic events, including histone modifications and DNA methylation, on a genome-wide scale. Like the identification of genetic mutations, mapping of changes to the epigenetic landscape has increased our understanding of cancer progression. However, in contrast to irreversible genetic mutations, epigenetic modifications are flexible and dynamic, thereby making them promising therapeutic targets. Ongoing studies are evaluating the use of epigenetic drugs in chemotherapy sensitization and immune system modulation. With the preclinical success of drugs that modify epigenetics, along with the FDA approval of epigenetic drugs including the DNA methyltransferase 1 (DNMT1) inhibitor 5-azacitidine and the histone deacetylase (HDAC) inhibitor vorinostat, there has been a rise in the number of drugs that target epigenetic modulators over recent years.
We provide an overview of epigenetic modulations, particularly those involved in cancer, and discuss the recent advances in drug development that target these chromatin-modifying events, primarily focusing on novel strategies to regulate the epigenome.
表观遗传改变包括关键的调节事件，这些事件可以动态地改变基因表达，其失调通常与各种疾病（包括癌症）的发病机制有关。与 DNA 突变不同，表观遗传改变涉及调节染色质结构的蛋白质和核酸的修饰，而不会影响基础 DNA 序列，改变转录机制对 DNA 的可及性，从而调节基因表达。在癌细胞中，这通常涉及肿瘤抑制基因的沉默或参与致癌的基因的表达增加。实验室医学的进步使得在全基因组范围内绘制关键的表观遗传事件（包括组蛋白修饰和 DNA 甲基化）成为可能。就像识别基因突变一样，对表观遗传景观变化的映射增加了我们对癌症进展的理解。然而，与不可逆的基因突变不同，表观遗传修饰具有灵活性和动态性，因此成为有前途的治疗靶点。正在进行的研究评估了在化疗增敏和免疫系统调节中使用表观遗传药物。随着改变表观遗传的药物在临床前的成功，以及 FDA 批准了包括 DNA 甲基转移酶 1（DNMT1）抑制剂 5-氮杂胞苷和组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他在内的表观遗传药物，近年来靶向表观遗传调节剂的药物数量有所增加。
我们概述了表观遗传修饰，特别是涉及癌症的修饰，并讨论了近年来针对这些染色质修饰事件的药物开发的最新进展，主要侧重于调节表观基因组的新策略。
