Han Mei, Jia Lina, Lv Wencai, Wang Lihui, Cui Wei
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
Front Oncol. 2019 Mar 29;9:194. doi: 10.3389/fonc.2019.00194. eCollection 2019.
Epigenetic modifications, such as DNA methylation and histone modification, result in heritable changes in gene expression without changing the DNA sequence. Epigenetic regulatory enzymes such as DNA methyltransferases, histone methyltransferases, and histone deacetylases are involved in epigenetic modification. Studies have shown that the dysregulation caused by changes in the amino acid sequence of these enzymes is closely correlated with tumor onset and progression. In addition, certain amino acid changes in the metabolic enzyme isocitrate dehydrogenase (IDH) are linked to altered epigenetic modifications in tumors. Some small molecule inhibitors targeting these aberrant enzymes have shown promising anti-cancer efficacy in preclinical and clinical trials. For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia. In this review, we summarize the recurrent "hotspot" mutations in these enzymes in various tumors and their role in tumorigenesis. We also describe candidate inhibitors of the mutant enzymes which show potential therapeutic value. In addition, we introduce some previously unreported mutation sites in these enzymes, which may be related to tumor development and provide opportunities for future study.
表观遗传修饰，如DNA甲基化和组蛋白修饰，可导致基因表达的可遗传变化，而不改变DNA序列。DNA甲基转移酶、组蛋白甲基转移酶和组蛋白去乙酰化酶等表观遗传调节酶参与表观遗传修饰。研究表明，这些酶的氨基酸序列变化引起的失调与肿瘤的发生和进展密切相关。此外，代谢酶异柠檬酸脱氢酶（IDH）的某些氨基酸变化与肿瘤中表观遗传修饰的改变有关。一些针对这些异常酶的小分子抑制剂在临床前和临床试验中已显示出有前景的抗癌疗效。例如，靶向R132位点突变的IDH1的小分子抑制剂艾伏尼布已被美国食品药品监督管理局（FDA）批准用于急性髓系白血病的临床治疗。在本综述中，我们总结了这些酶在各种肿瘤中反复出现的“热点”突变及其在肿瘤发生中的作用。我们还描述了显示出潜在治疗价值的突变酶的候选抑制剂。此外，我们介绍了这些酶中一些以前未报道的突变位点，这些位点可能与肿瘤发展有关，并为未来的研究提供了机会。
