Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Department of Pediatrics, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
FEBS J. 2022 Mar;289(5):1315-1328. doi: 10.1111/febs.15963. Epub 2021 May 24.
Since the discovery of recurrent mutations in histone H3 variants in paediatric brain tumours, so-called 'oncohistones' have been identified in various cancers. While their mechanism of action remains under active investigation, several studies have shed light on how they promote genome-wide epigenetic perturbations. These findings converge on altered post-translational modifications on two key lysine (K) residues of the H3 tail, K27 and K36, which regulate several cellular processes, including those linked to cell differentiation during development. We will review how these oncohistones affect the methylation of cognate residues, but also disrupt the distribution of opposing chromatin marks, creating genome-wide epigenetic changes which participate in the oncogenic process. Ultimately, tumorigenesis is promoted through the maintenance of a progenitor state at the expense of differentiation in defined cellular and developmental contexts. As these epigenetic disruptions are reversible, improved understanding of oncohistone pathogenicity can result in needed alternative therapies.
自发现组蛋白 H3 变异体在小儿脑肿瘤中的反复突变以来，各种癌症中已经鉴定出所谓的“癌组蛋白”。虽然它们的作用机制仍在积极研究中，但有几项研究阐明了它们如何促进全基因组表观遗传扰动。这些发现集中在 H3 尾部两个关键赖氨酸 (K) 残基 K27 和 K36 的翻译后修饰改变上，这些修饰调节包括发育过程中与细胞分化相关的多种细胞过程。我们将回顾这些癌组蛋白如何影响同源残基的甲基化，还会破坏相反染色质标记的分布，从而导致全基因组的表观遗传变化，参与致癌过程。最终，通过在特定细胞和发育环境中牺牲分化来维持祖细胞状态，促进肿瘤发生。由于这些表观遗传破坏是可逆的，因此更好地了解癌组蛋白的致病性可以导致需要的替代疗法。
