Jin Ping, Chen Xiaofei
Shenzhen Maternity & Child Healthcare Hospital Affiliated to Southern Medical University, Shenzhen, 518028, China.
Anticancer Agents Med Chem. 2016;16(6):699-712. doi: 10.2174/1871520616666151116124432.
In recent years, there has been an expansion of the understanding of how epigenetic dysregulation plays a role in tumorigenesis, progression, metastasis and treatment resistance. Evidence has focused on two common and well-studied "epigenetic codes", i.e., DNA methylation and histone posttranslational modification, which regulate the transcriptional status in various types of cancer and the corresponding target agents. Aside from "writers" and "erasers", which refer to enzymes that catalyze and remove posttranslational modifications, respectively, "readers" bind to target proteins and recruit "writers" and "erasers" for regulating gene expression. A number of selective and potent anticancer compounds have been reported, some of which are in preclinical or clinical trials that have shown promising results, primarily against malignant neoplasms such as hematologic malignancies, with the subsequent emerging development of both monotherapy and co-administration with traditional cytotoxic medicines against solid tumors. Second-generation epigenetic agents such as EZH2 and BET inhibitors have greatly progressed. Epigenetic dysregulation has also provided feasibility for the diagnosis and treatment of cancer. In this review, we summarize the progress in epigenetics and drug discovery for cancer and certain clinical trials that may provide a perspective for future development.
近年来，人们对于表观遗传失调在肿瘤发生、进展、转移和治疗耐药性中所起作用的认识不断扩展。证据主要集中在两种常见且研究充分的“表观遗传密码”，即DNA甲基化和组蛋白翻译后修饰，它们在各类癌症中调节转录状态以及相应的靶向药物。除了分别指催化和去除翻译后修饰的酶的“书写者”和“擦除者”之外，“阅读者”与靶蛋白结合并招募“书写者”和“擦除者”来调节基因表达。已经报道了许多选择性强效抗癌化合物，其中一些正处于临床前或临床试验阶段，已显示出有前景的结果，主要针对血液系统恶性肿瘤等恶性肿瘤，随后出现了单药治疗以及与传统细胞毒性药物联合用于实体瘤治疗的新进展。第二代表观遗传药物如EZH2和BET抑制剂取得了很大进展。表观遗传失调也为癌症的诊断和治疗提供了可行性。在本综述中，我们总结了癌症表观遗传学和药物发现方面的进展以及某些临床试验，这些可能为未来发展提供一个视角。
