Kondo Yutaka
Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
J Biochem. 2014 Nov;156(5):249-57. doi: 10.1093/jb/mvu054. Epub 2014 Aug 31.
It is widely accepted that epigenetic alterations are associated with different stages of tumour formation and progression in many cancers. Therefore, epigenetic abnormalities in cancers are emerging as important biomarkers and may have therapeutic potential. The polycomb repressive complex 2 (PRC2) is a key epigenetic regulator that catalyses trimethylation of lysine 27 on histone H3 (H3K27me3) via the histone methyltransferase, EZH2, which confers stemness and regulates differentiation during embryonic development. Given these roles of EZH2 and H3K27me3, plastic and dynamic features of cancer cells, especially cancer stem cells (CSCs), may be closely associated with this epigenetic mechanism. In addition, recent sequencing technology revealed that there are many recurrent mutations in polycomb-related genes, including EZH2, in different types of cancers. Therefore, researchers focused on targeting EZH2 as a novel cancer treatment and identified small compounds that inhibit EZH2 activity. Some of them are now under clinical trial in B-cell lymphoma. However, the underlying mechanisms by which PRC2 precisely regulate epigenetic alterations at certain genomic loci under different cellular conditions remain unclear. In this review, I focus on the recent advancements in EZH2 research, especially its dynamic regulation of epigenetic alterations in tumour cells, including the CSC population, and discuss perspectives and challenges for cancer treatment in the near future.
人们普遍认为，表观遗传改变与许多癌症肿瘤形成和进展的不同阶段相关。因此，癌症中的表观遗传异常正成为重要的生物标志物，并且可能具有治疗潜力。多梳抑制复合物2（PRC2）是一种关键的表观遗传调节因子，它通过组蛋白甲基转移酶EZH2催化组蛋白H3上赖氨酸27的三甲基化（H3K27me3），这赋予了干性并在胚胎发育过程中调节分化。鉴于EZH2和H3K27me3的这些作用，癌细胞，尤其是癌症干细胞（CSC）的可塑性和动态特征可能与这种表观遗传机制密切相关。此外，最近的测序技术表明，在不同类型的癌症中，包括EZH2在内的多梳相关基因存在许多反复出现的突变。因此，研究人员将重点放在靶向EZH2作为一种新型癌症治疗方法上，并鉴定出了抑制EZH2活性的小分子化合物。其中一些目前正在进行B细胞淋巴瘤的临床试验。然而，PRC2在不同细胞条件下精确调节某些基因组位点表观遗传改变的潜在机制仍不清楚。在这篇综述中，我重点关注EZH2研究的最新进展，特别是其对肿瘤细胞（包括CSC群体）表观遗传改变的动态调节，并讨论近期癌症治疗的前景和挑战。
