Department of Pulmonary Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Int J Oncol. 2010 Dec;37(6):1537-46. doi: 10.3892/ijo_00000807.
Epigenetic gene regulation plays essential roles in differentiation of embryonic and tissue stem cells. In these benign undifferentiated cells, some polycomb targeted genes are kept in a state of DNA hypomethylation and they have a distinct chromatin signature termed bivalent chromatin structure to maintain their plasticity. We hypothesized that cancer stem cells (CSC), the malignant counterpart of these cells, are also under the control of epigenetics like benign stem cells. We compared the DNA methylation and chromatin structure in 10 tumor suppressor genes between CSC and differentiated cancer cells of MCF7 and Huh7 cells. We found that the level of DNA methylation was indeed significantly lower in CSC, while surprisingly, the bivalent chromatin structure was more ubiquitously seen in differentiated cancer cells compared to CSC. However, repressive marks of chromatin structure, namely H3K27me3 and EZH2, were significantly lower in CSC. As a consequence, CSC remained in a higher transcriptionally active chromatin state compared to differentiated cancer cells. We found that the differentiation of CSCs is also epigenetically regulated. These findings could help towards a comprehensive understanding of CSC, and also improve the development of eradicative therapies against human malignancies.
表观遗传基因调控在胚胎和组织干细胞的分化中起着至关重要的作用。在这些良性未分化的细胞中，一些多梳靶向基因保持在 DNA 低甲基化的状态，它们具有一种独特的染色质特征，称为双价染色质结构，以维持其可塑性。我们假设，癌症干细胞（CSC）作为这些细胞的恶性对应物，也像良性干细胞一样受到表观遗传的控制。我们比较了 MCF7 和 Huh7 细胞中 10 个肿瘤抑制基因在 CSC 和分化癌细胞中的 DNA 甲基化和染色质结构。我们发现 CSC 中的 DNA 甲基化水平确实明显降低，而令人惊讶的是，与 CSC 相比，分化癌细胞中更普遍存在双价染色质结构。然而，染色质结构的抑制性标记，即 H3K27me3 和 EZH2，在 CSC 中明显降低。因此，CSC 保持了比分化癌细胞更高的转录活性染色质状态。我们发现 CSC 的分化也是受表观遗传调控的。这些发现有助于全面了解 CSC，也有助于开发针对人类恶性肿瘤的根除性治疗方法。
