Li Dong, Shi Jiejun, Du Yanhua, Chen Kaiming, Liu Zhenping, Li Bing, Li Jie, Tao Fei, Gu Hua, Jiang Cizhong, Fang Jianmin
School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
The Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
PLoS One. 2016 Jun 30;11(6):e0158214. doi: 10.1371/journal.pone.0158214. eCollection 2016.
Tumor cells become resistant after long-term use of anti-VEGF (vascular endothelial growth factor) agents. Our previous study shows that treatment with a VEGF inhibitor (VEGF-Trap) facilitates to develop tumor resistance through regulating angiogenesis-related genes. However, the underlying molecular mechanisms remain elusive. Histone modifications as a key epigenetic factor play a critical role in regulation of gene expression. Here, we explore the potential epigenetic gene regulatory functions of key histone modifications during tumor resistance in a mouse Lewis lung carcinoma (LLC) cell line. We generated high resolution genome-wide maps of key histone modifications in sensitive tumor sample (LLC-NR) and resistant tumor sample (LLC-R) after VEGF-Trap treatment. Profiling analysis of histone modifications shows that histone modification levels are effectively predictive for gene expression. Composition of promoters classified by histone modification state is different between LLC-NR and LLC-R cell lines regardless of CpG content. Histone modification state change between LLC-NR and LLC-R cell lines shows different patterns in CpG-rich and CpG-poor promoters. As a consequence, genes with different level of CpG content whose gene expression level are altered are enriched in distinct functions. Notably, histone modification state change in promoters of angiogenesis-related genes consists with their expression alteration. Taken together, our findings suggest that treatment with anti-VEGF therapy results in extensive histone modification state change in promoters with multiple functions, particularly, biological processes related to angiogenesis, likely contributing to tumor resistance development.
长期使用抗血管内皮生长因子（VEGF）药物后肿瘤细胞会产生耐药性。我们之前的研究表明，用VEGF抑制剂（VEGF-Trap）治疗会通过调节血管生成相关基因促进肿瘤耐药性的产生。然而，其潜在的分子机制仍不清楚。组蛋白修饰作为关键的表观遗传因子在基因表达调控中起关键作用。在此，我们在小鼠Lewis肺癌（LLC）细胞系中探索关键组蛋白修饰在肿瘤耐药过程中潜在的表观遗传基因调控功能。我们绘制了VEGF-Trap治疗后敏感肿瘤样本（LLC-NR）和耐药肿瘤样本（LLC-R）中关键组蛋白修饰的高分辨率全基因组图谱。组蛋白修饰的分析表明，组蛋白修饰水平可有效预测基因表达。无论CpG含量如何，LLC-NR和LLC-R细胞系中按组蛋白修饰状态分类的启动子组成都不同。LLC-NR和LLC-R细胞系之间的组蛋白修饰状态变化在富含CpG和缺乏CpG的启动子中呈现不同模式。因此，CpG含量不同且基因表达水平发生改变的基因在不同功能中富集。值得注意的是，血管生成相关基因启动子中的组蛋白修饰状态变化与其表达改变一致。综上所述，我们的研究结果表明，抗VEGF治疗导致具有多种功能的启动子中广泛的组蛋白修饰状态变化，特别是与血管生成相关的生物学过程，这可能有助于肿瘤耐药性的发展。
