Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
Mayo Clinic, Rochester, MN 55902, USA.
Cells. 2022 Oct 26;11(21):3376. doi: 10.3390/cells11213376.
Histone post-translational modifications modulate gene expression through epigenetic gene regulation. The core histone H3 family members, H3.1, H3.2, and H3.3, play a central role in epigenetics. H3 histones can acquire many post-translational modifications, including the trimethylation of H3K27 (H3K27me3), which represses transcription. Triple methylation of H3K27 is performed by the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the Polycomb Repressive Complex 2. Both global increases and decreases in H3K27me3 have been implicated in a wide range of cancer types. Here, we explore how opposing changes in H3K27me3 contribute to cancer by highlighting its role in two vastly different cancer types; (1) a form of glioma known as diffuse midline glioma H3K27-altered and (2) epithelial ovarian cancer. These two cancers vary widely in the age of onset, sex, associated mutations, and cell and organ type. However, both diffuse midline glioma and ovarian cancer have dysregulation of H3K27 methylation, triggering changes to the cancer cell transcriptome. In diffuse midline glioma, the loss of H3K27 methylation is a primary driving factor in tumorigenesis that promotes glial cell stemness and silences tumor suppressor genes. Conversely, hypermethylation of H3K27 occurs in late-stage epithelial ovarian cancer, which promotes tumor vascularization and tumor cell migration. By using each cancer type as a case study, this review emphasizes the importance of H3K27me3 in cancer while demonstrating that the mechanisms of histone H3 modification and subsequent gene expression changes are not a one-size-fits-all across cancer types.
组蛋白翻译后修饰通过表观遗传基因调控调节基因表达。核心组蛋白 H3 家族成员 H3.1、H3.2 和 H3.3 在表观遗传学中发挥核心作用。H3 组蛋白可以获得许多翻译后修饰，包括 H3K27 的三甲基化（H3K27me3），其抑制转录。H3K27 的三甲基化由组蛋白甲基转移酶 Enhancer of Zeste Homologue 2（EZH2）完成，EZH2 是 Polycomb Repressive Complex 2 的一个组成部分。H3K27me3 的全局增加和减少都与多种癌症类型有关。在这里，我们通过突出其在两种截然不同的癌症类型中的作用来探讨 H3K27me3 的相反变化如何促进癌症：（1）一种称为弥漫性中线胶质瘤 H3K27 改变的神经胶质瘤，（2）上皮性卵巢癌。这两种癌症在发病年龄、性别、相关突变以及细胞和器官类型上差异很大。然而，弥漫性中线胶质瘤和卵巢癌都存在 H3K27 甲基化的失调，引发癌细胞转录组的变化。在弥漫性中线胶质瘤中，H3K27 甲基化的丧失是肿瘤发生的主要驱动因素，促进神经胶质细胞干性并沉默肿瘤抑制基因。相反，H3K27 的高甲基化发生在晚期上皮性卵巢癌中，促进肿瘤血管生成和肿瘤细胞迁移。通过将每种癌症类型用作案例研究，本综述强调了 H3K27me3 在癌症中的重要性，同时表明组蛋白 H3 修饰的机制和随后的基因表达变化在癌症类型之间并不是一刀切的。
