H3K27 Methylation: A Focal Point of Epigenetic Deregulation in Cancer.

Epigenetics, the modification of chromatin without changing the DNA sequence itself, determines whether a gene is expressed, and how much of a gene is expressed. Methylation of lysine 27 on histone 3 (H3K27me), a modification usually associated with gene repression, has established roles in regulating the expression of genes involved in lineage commitment and differentiation. Not surprisingly, alterations in the homeostasis of this critical mark have emerged as a recurrent theme in the pathogenesis of many cancers. Perturbations in the distribution or levels of H3K27me occur due to deregulation at all levels of the process, either by mutation in the histone itself, or changes in the activity of the writers, erasers or readers of this mark. Additionally, as no single histone mark alone determines the overall transcriptional readiness of a chromatin region, deregulation of other chromatin marks can also have dramatic consequences. Finally, the significance of mutations altering H3K27me is highlighted by the poor clinical outcome of patients whose tumors harbor such lesions. Current therapeutic approaches targeting aberrant H3K27 methylation remain to be proven useful in the clinic. Understanding the biological consequences and gene expression pathways affected by aberrant H3K27 methylation may lead to identification of new therapeutic targets and strategies.

表观遗传学是指在不改变DNA序列本身的情况下对染色质进行修饰，它决定了一个基因是否表达以及表达量的多少。组蛋白3上赖氨酸27的甲基化（H3K27me）是一种通常与基因抑制相关的修饰，在调控参与谱系定型和分化的基因表达方面具有确定的作用。毫不奇怪，这种关键标记的内稳态改变已成为许多癌症发病机制中反复出现的主题。H3K27me的分布或水平发生扰动是由于该过程各个层面的失调，要么是组蛋白本身发生突变，要么是这种标记的“书写者”“擦除者”或“读取者”的活性发生变化。此外，由于没有单个组蛋白标记单独决定染色质区域的整体转录就绪状态，其他染色质标记的失调也可能产生重大影响。最后，肿瘤存在此类病变的患者临床预后不良，凸显了改变H3K27me的突变的重要性。目前针对异常H3K27甲基化的治疗方法在临床上是否有用仍有待证明。了解异常H3K27甲基化所影响的生物学后果和基因表达途径可能会导致新的治疗靶点和策略的确定。