Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic.
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic.
Cells. 2020 Jun 24;9(6):1540. doi: 10.3390/cells9061540.
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.
结直肠癌（CRC）的发生是由遗传和表观遗传改变的逐渐长期积累引起的。最近，表观遗传改变已被纳入 CRC 分子亚型的分类，这指出了它们的预后影响。由于表观遗传修饰是可逆的，它们可能代表相关的治疗靶点。DNA 甲基化由 DNA 甲基转移酶（DNMTs）催化，调节基因表达。多年来，DNA 甲基化的失调被认为在 CRC 的病因学和演变中起着重要作用。尽管 CRC 的治疗取得了相当大的进展，但患者的治疗反应仍然有限，他们从系统治疗中获益往往受到化疗耐药性的阻碍。此外，CRC 患者治疗反应的个体间差异可能源于他们特定的（表观）遗传组成。在这篇综述文章中，我们根据 DNA 甲基化状态总结了 CRC 治疗的选择及其预测价值。这篇综述还包括基于 CRC 患者甲基化状态的治疗结果。此外，目前的研究挑战是开发 DNMT 的治疗抑制剂。基于 DNA 甲基化在 CRC 发展中的重要作用，最近提出了应用 DNMT 抑制剂治疗 CRC 患者，特别是 DNA 过度甲基化的患者。
