Epigenetics Group, International Agency for Research on Cancer ,69008 Lyon, France.
Adv Genet. 2010;70:57-85. doi: 10.1016/B978-0-12-380866-0.60003-4.
It is now widely recognized that epigenetic events are important mechanisms underlying cancer development and progression. Epigenetic information in chromatin includes covalent modifications (such as acetylation, methylation, phosphorylation, and ubiquitination) of core nucleosomal proteins (histones). A recent progress in the field of histone modifications and chromatin research has tremendously enhanced our understanding of the mechanisms underlying the control of key physiological and pathological processes. Histone modifications and other epigenetic mechanisms appear to work together in establishing and maintaining gene activity states, thus regulating a wide range of cellular processes. Different histone modifications themselves act in a coordinated and orderly fashion to regulate cellular processes such as gene transcription, DNA replication, and DNA repair. Interest in histone modifications has further grown over the last decade with the discovery and characterization of a large number of histone-modifying molecules and protein complexes. Alterations in the function of histone-modifying complexes are believed to disrupt the pattern and levels of histone marks and consequently deregulate the control of chromatin-based processes, ultimately leading to oncogenic transformation and the development of cancer. Consistent with this notion, aberrant patterns of histone modifications have been associated with a large number of human malignancies. In this chapter, we discuss recent advances in our understanding of the mechanisms controlling the establishment and maintenance of histone marks and how disruptions of these chromatin-based mechanisms contribute to tumorigenesis. We also suggest how these advances may facilitate the development of novel strategies to prevent, diagnose, and treat human malignancies.
现在人们普遍认为，表观遗传事件是癌症发生和发展的重要机制。染色质中的表观遗传信息包括核心核小体蛋白（组蛋白）的共价修饰（如乙酰化、甲基化、磷酸化和泛素化）。组蛋白修饰和染色质研究领域的最新进展极大地增强了我们对控制关键生理和病理过程的机制的理解。组蛋白修饰和其他表观遗传机制似乎共同作用于建立和维持基因活性状态，从而调节广泛的细胞过程。不同的组蛋白修饰本身以协调和有序的方式共同作用，以调节细胞过程，如基因转录、DNA 复制和 DNA 修复。在过去的十年中，随着大量组蛋白修饰分子和蛋白复合物的发现和表征，人们对组蛋白修饰的兴趣进一步增加。人们相信，组蛋白修饰复合物功能的改变会破坏组蛋白标记的模式和水平，从而导致染色质相关过程的失控，最终导致致癌转化和癌症的发展。与这一观点一致的是，异常的组蛋白修饰模式与大量人类恶性肿瘤有关。在本章中，我们讨论了我们对控制组蛋白标记建立和维持的机制的理解的最新进展，以及这些染色质机制的破坏如何导致肿瘤发生。我们还提出了这些进展如何有助于开发预防、诊断和治疗人类恶性肿瘤的新策略。
