Department of Neurosurgery, Nagoya University School of Medicine, Divisions of Epigenomics and Molecular Oncology, Aichi Cancer Center Research Institute.
Cancer Res. 2013 Jul 15;73(14):4559-70. doi: 10.1158/0008-5472.CAN-13-0109. Epub 2013 May 29.
Tumor cell plasticity contributes to functional and morphologic heterogeneity. To uncover the underlying mechanisms of this plasticity, we examined glioma stem-like cells (GSC) where we found that the biologic interconversion between GSCs and differentiated non-GSCs is functionally plastic and accompanied by gain or loss of polycomb repressive complex 2 (PRC2), a complex that modifies chromatin structure. PRC2 mediates lysine 27 trimethylation on histone H3 and in GSC it affected pluripotency or development-associated genes (e.g., Nanog, Wnt1, and BMP5) together with alterations in the subcellular localization of EZH2, a catalytic component of PRC2. Intriguingly, exogenous expression of EZH2-dNLS, which lacks nuclear localization sequence, impaired the repression of Nanog expression under differentiation conditions. RNA interference (RNAi)-mediated attenuation or pharmacologic inhibition of EZH2 had little to no effect on apoptosis or bromodeoxyuridine incorporation in GSCs, but it disrupted morphologic interconversion and impaired GSC integration into the brain tissue, thereby improving survival of GSC-bearing mice. Pathologic analysis of human glioma specimens revealed that the number of tumor cells with nuclear EZH2 is larger around tumor vessels and the invasive front, suggesting that nuclear EZH2 may help reprogram tumor cells in close proximity to this microenvironment. Our results indicate that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity, which is required for the adaptation of glioblastoma cells to their microenvironment. Thus, PRC2-targeted therapy may reduce tumor cell plasticity and tumor heterogeneity, offering a new paradigm for glioma treatment.
肿瘤细胞的可塑性有助于功能和形态的异质性。为了揭示这种可塑性的潜在机制，我们研究了神经胶质瘤干细胞（GSC），在这些细胞中，我们发现 GSC 和分化的非 GSC 之间的生物学转化是功能上可塑的，并伴随着多梳抑制复合物 2（PRC2）的获得或丧失，PRC2 修饰染色质结构。PRC2 介导组蛋白 H3 赖氨酸 27 的三甲基化，在 GSC 中，它影响多能性或与发育相关的基因（例如 Nanog、Wnt1 和 BMP5），同时 EZH2 的亚细胞定位发生改变，EZH2 是 PRC2 的催化亚基。有趣的是，表达缺乏核定位序列的 EZH2-dNLS 会损害分化条件下 Nanog 表达的抑制。RNA 干扰（RNAi）介导的 EZH2 衰减或药理学抑制对 GSC 中的细胞凋亡或溴脱氧尿苷掺入几乎没有影响，但它破坏了形态转化并损害了 GSC 整合到脑组织中的能力，从而提高了携带 GSC 小鼠的存活率。对人类脑肿瘤标本的病理分析表明，在肿瘤血管和侵袭前沿周围，具有核 EZH2 的肿瘤细胞数量更多，这表明核 EZH2 可能有助于重新编程靠近这种微环境的肿瘤细胞。我们的结果表明，PRC2 的表观遗传调控是肿瘤细胞可塑性的关键介质，这对于神经胶质瘤细胞适应其微环境是必需的。因此，针对 PRC2 的治疗可能会降低肿瘤细胞的可塑性和肿瘤异质性，为治疗脑肿瘤提供了新的范例。
