Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition
Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition
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DOI：
10.4161/cc.25163
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发表时间：
2013-07-01
期刊：
影响因子：
4.3
通讯作者：
Zhang, Rugang
中科院分区：
文献类型：
--
作者：
Amatangelo, Michael D.;Garipov, Azat;Zhang, Rugang
EZH2甲基转移酶活性抑制剂已被证明可以选择性地抑制EZH2功能获得突变的弥漫性大B细胞淋巴瘤（DLBCL）细胞的生长，而对EZH2野生型DLBCL细胞的生长影响非常有限。鉴于EZH2在实体瘤中经常过度表达而不突变，研究实体瘤细胞对EZH2抑制剂敏感性的决定因素是很重要的。在目前的研究中，我们发现三维（3D）培养过表达EZH2的上皮性卵巢癌（EOC）细胞使这些细胞对EZH2甲基转移酶抑制敏感。用EZH2甲基转移酶特异性抑制剂GSK343处理EOC细胞，降低EZH2酶活性产物H3K27Me3的水平。然而，在常规二维（2D）培养中，GSK343对EOC细胞生长的影响有限。相比之下，GSK343显著抑制了3D基质细胞外基质（ECM）中培养的EOC细胞的生长，ECM更接近于体内肿瘤微环境。值得注意的是，GSK343在3D培养中诱导EOC细胞凋亡，而在2D培养中没有。此外，GSK343还能显著抑制EOC细胞的侵袭。总之，我们发现3D ECM使EOC细胞对EZH2甲基转移酶抑制敏感，从而抑制细胞生长，诱导细胞凋亡并抑制侵袭。我们的研究结果表明，在EZH2野生型实体瘤中，ECM肿瘤微环境在决定EZH2抑制剂的敏感性方面起着重要作用，并且表明靶向ECM是增强EZH2抑制剂疗效的一种新策略。
Inhibitors of EZH2 methyltransferase activity have been demonstrated to selectively suppress the growth of diffused large B cell lymphoma (DLBCL) cells with gain-of-function mutations in EZH2, while exhibiting very limited effects on the growth of DLBCL cells with wild-type EZH2. Given that EZH2 is often overexpressed but not mutated in solid tumors, it is important to investigate the determinants of sensitivity of solid tumor cells to EZH2 inhibitors. In the current study, we show that three-dimensional (3D) culture of epithelial ovarian cancer (EOC) cells that overexpress EZH2 sensitizes these cells to EZH2 methyltransferase inhibition. Treatment of EOC cells with GSK343, a specific inhibitor of EZH2 methyltransferase, decreases the level of H3K27Me3, the product of EZH2's enzymatic activity. However, GSK343 exhibited limited effects on the growth of EOC cells in conventional two-dimensional (2D) culture. In contrast, GSK343 significantly suppressed the growth of EOC cells cultured in 3D matrigel extracellular matrix (ECM), which more closely mimics the tumor microenvironment in vivo. Notably, GSK343 induces apoptosis of EOC cells in 3D but not 2D culture. In addition, GSK343 significantly inhibited the invasion of EOC cells. In summary, we show that the 3D ECM sensitizes EOC cells to EZH2 methyltransferase inhibition, which suppresses cell growth, induces apoptosis and inhibits invasion. Our findings imply that in EZH2 wild-type solid tumors, the ECM tumor microenvironment plays an important role in determining sensitivity to EZH2 inhibition and suggest that targeting the ECM represents a novel strategy for enhancing EZH2 inhibitor efficacy.