Department of Biochemistry and Molecular Biology, University of Louisville, 580 South Preston Street, Suite 221, Louisville, KY 40202, USA.
Cancer Treat Rev. 2014 Feb;40(1):153-69. doi: 10.1016/j.ctrv.2013.05.009. Epub 2013 Jul 5.
Genetic mutations and gross structural defects in the DNA sequence permanently alter genetic loci in ways that significantly disrupt gene function. In sharp contrast, genes modified by aberrant epigenetic modifications remain structurally intact and are subject to partial or complete reversal of modifications that restore the original (i.e. non-diseased) state. Such reversibility makes epigenetic modifications ideal targets for therapeutic intervention. The epigenome of cancer cells is extensively modified by specific hypermethylation of the promoters of tumor suppressor genes relative to the extensive hypomethylation of repetitive sequences, overall loss of acetylation, and loss of repressive marks at microsatellite/repeat regions. In this review, we discuss emerging therapies targeting specific epigenetic modifications or epigenetic modifying enzymes either alone or in combination with other treatment regimens. The limitations posed by cancer treatments elicit unintended epigenetic modifications that result in exacerbation of tumor progression are also discussed. Lastly, a brief discussion of the specificity restrictions posed by epigenetic therapies and ways to address such limitations is presented.
遗传突变和 DNA 序列中的大体结构缺陷会永久性地改变遗传基因座，从而严重破坏基因功能。相比之下，通过异常的表观遗传修饰修饰的基因在结构上保持完整，并可对修饰进行部分或完全逆转，从而恢复原始（即非疾病）状态。这种可逆性使表观遗传修饰成为治疗干预的理想靶点。癌细胞的表观基因组通过肿瘤抑制基因启动子的特定高甲基化相对于重复序列的广泛低甲基化、整体去乙酰化以及微卫星/重复区域抑制性标记的丢失而广泛修饰。在这篇综述中，我们讨论了针对特定表观遗传修饰或表观遗传修饰酶的新兴疗法，无论是单独使用还是与其他治疗方案联合使用。还讨论了癌症治疗引起的意外表观遗传修饰导致肿瘤进展恶化所带来的局限性。最后，简要讨论了表观遗传疗法带来的特异性限制以及解决这些限制的方法。
