Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies.
Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies.
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DOI：
10.1186/1479-5876-8-56
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发表时间：
2010-06-11
影响因子：
7.4
通讯作者：
Maio M
中科院分区：
文献类型：
--
作者：
Sigalotti L;Covre A;Fratta E;Parisi G;Colizzi F;Rizzo A;Danielli R;Nicolay HJ;Coral S;Maio M
皮肤黑色素瘤是一种非常侵袭性的黑色素细胞来源的肿瘤，在世界范围内发病率和死亡率不断上升。最近发现表观遗传修饰（即基因组 DNA 甲基化模式、组蛋白翻译后修饰和 microRNA 图谱的改变）通过影响细胞周期调节、细胞信号传导、分化、DNA 修复、细胞凋亡、侵袭和免疫识别等关键细胞途径，在黑色素瘤的发生和进展中发挥着重要作用。在这种情况下，DNA甲基转移酶和/或组蛋白脱乙酰酶的药物抑制被证明可以有效恢复异常沉默基因的表达，从而重建通路功能。鉴于表观遗传药物的多效性活性，强烈建议将它们单独使用或联合治疗，并且预计它们与黑色素瘤患者的化疗、放射和免疫治疗方法的协同活性可能会产生特殊的临床益处。在这条道路上，重要的改进可能来自于新一代表观遗传药物的开发，这些药物的特点是系统毒性大大降低、生物利用度更高、表观遗传效应更特异。
Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects.
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