Atkinson Stuart P, Keith W Nicol
Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Bearsden, Glasgow, G61 1BD, UK.
Expert Rev Mol Med. 2007 Mar 13;9(7):1-26. doi: 10.1017/S1462399407000269.
Understanding how senescence is established and maintained is an important area of study both for normal cell physiology and in tumourigenesis. Modifications to N-terminal tails of histone proteins, which can lead to chromatin remodelling, appear to be key to the regulation of the senescence phenotype. Epigenetic mechanisms such as modification of histone proteins have been shown to be sufficient to regulate gene expression levels and specific gene promoters can become epigenetically altered at senescence. This suggests that epigenetic mechanisms are important in senescence and further suggests epigenetic deregulation could play an important role in the bypass of senescence and the acquisition of a tumourigenic phenotype. Tumour suppressor proteins and cellular senescence are intimately linked and such proteins are now known to regulate gene expression through chromatin remodelling, again suggesting a link between chromatin modification and cellular senescence. Telomere dynamics and the expression of the telomerase genes are also both implicitly linked to senescence and tumourigenesis, and epigenetic deregulation of the telomerase gene promoters has been identified as a possible mechanism for the activation of telomere maintenance mechanisms in cancer. Recent studies have also suggested that epigenetic deregulation in stem cells could play an important role in carcinogenesis, and new models have been suggested for the attainment of tumourigenesis and bypass of senescence. Overall, proper regulation of the chromatin environment is suggested to have an important role in the senescence pathway, such that its deregulation could lead to tumourigenesis.
了解衰老如何建立和维持，无论是对于正常细胞生理学还是肿瘤发生学来说，都是一个重要的研究领域。组蛋白N端尾巴的修饰可导致染色质重塑，这似乎是衰老表型调控的关键。诸如组蛋白修饰等表观遗传机制已被证明足以调节基因表达水平，并且特定基因启动子在衰老时可发生表观遗传改变。这表明表观遗传机制在衰老过程中很重要，进一步表明表观遗传失调可能在衰老的绕过和致瘤表型的获得中发挥重要作用。肿瘤抑制蛋白与细胞衰老密切相关，现在已知这类蛋白通过染色质重塑来调节基因表达，这再次表明染色质修饰与细胞衰老之间存在联系。端粒动态变化和端粒酶基因的表达也都与衰老和肿瘤发生隐含相关，并且端粒酶基因启动子的表观遗传失调已被确定为癌症中端粒维持机制激活的一种可能机制。最近的研究还表明，干细胞中的表观遗传失调可能在致癌过程中起重要作用，并且已经提出了关于获得肿瘤发生和绕过衰老的新模型。总体而言，染色质环境的适当调节在衰老途径中似乎起着重要作用，因此其失调可能导致肿瘤发生。
