Abigail V. Lee , Kevin A. Nestler , Katherine B. Chiappinelli
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引用次数: 0
摘要
DNA 甲基化是基因调控的重要组成部分,在癌症的发展中扮演着重要角色。肿瘤抑制基因的过度甲基化和DNA修复途径的沉默会促进细胞的失控生长,并与致癌突变协同作用,使癌症表型永久化。此外,DNA 甲基化异常还会阻碍对抗肿瘤免疫至关重要的免疫反应。因此,抑制失调的 DNA 甲基化是一种很有前景的癌症疗法。对 DNA 甲基化的药物抑制可重新激活沉默的肿瘤抑制因子,并通过诱导病毒模拟来增强免疫反应。现在,随着免疫疗法的出现和 DNA 甲基化抑制剂免疫调节作用的发现,人们对了解 DNA 甲基化靶向与其他疗法的结合如何增强抗肿瘤免疫产生了浓厚的兴趣。在此,我们将介绍 DNA 甲基化异常在癌症中的作用,以及促进肿瘤发生和调节免疫反应的机制。最后,我们回顾了针对 DNA 甲基化作为癌症疗法的初步发现和正在进行的努力。
Therapeutic targeting of DNA methylation alterations in cancer
DNA methylation is a critical component of gene regulation and plays an important role in the development of cancer. Hypermethylation of tumor suppressor genes and silencing of DNA repair pathways facilitate uncontrolled cell growth and synergize with oncogenic mutations to perpetuate cancer phenotypes. Additionally, aberrant DNA methylation hinders immune responses crucial for antitumor immunity. Thus, inhibiting dysregulated DNA methylation is a promising cancer therapy. Pharmacologic inhibition of DNA methylation reactivates silenced tumor suppressors and bolster immune responses through induction of viral mimicry. Now, with the advent of immunotherapies and discovery of the immune-modulatory effects of DNA methylation inhibitors, there is great interest in understanding how targeting DNA methylation in combination with other therapies can enhance antitumor immunity. Here, we describe the role of aberrant DNA methylation in cancer and mechanisms by which it promotes tumorigenesis and modulates immune responses. Finally, we review the initial discoveries and ongoing efforts to target DNA methylation as a cancer therapeutic.
期刊介绍:
Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.