title: Profiling Analysis of Histone Modifications and Gene Expression in Lewis Lung Carcinoma Murine Cells Resistant to Anti-VEGF Treatment.
abstract: 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.
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: The Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
authors.forename: Jiejun
authors.initials: J
authors.lastname: Shi
authors.affiliation: The Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Du
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Kaiming
authors.initials: K
authors.lastname: Chen
authors.affiliation: The Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Tao
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.affiliation: The Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory of Signaling and Disease Research, Tongji University, Shanghai, 200092, China.
authors.forename: Cizhong
authors.initials: C
authors.lastname: Jiang
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D042421:Histone Code / Q000187:drug effects*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
chemical_list: D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor