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.
Highlights
Lung cancer is the most commonly diagnosed human cancer worldwide and accounts for 1.6 million of total new cancer cases and caused about 1.4 million of cancer-related deaths all over the world in 2008 [1]
Lewis lung carcinoma (LLC)-R and LLC-NR cells (5 × 105 cells/ mouse) were subcutaneously inoculated into the right flanks of C57BL/6J mice (n = 10/group, total 20 mice) to allow tumor isografts to grow to an approximate size of 500 mm3 (tumor volume =/2) and tumor isograft tissues were dissected and used for further study
Our results show that the occupancy level of active histone marks (H3K4me3 and H3K9ac) are positively correlated with gene expression whereas repressive histone mark (H3K27me3) is negatively correlated with gene expression (Fig 1)
Summary
Lung cancer is the most commonly diagnosed human cancer worldwide and accounts for 1.6 million of total new cancer cases and caused about 1.4 million of cancer-related deaths all over the world in 2008 [1]. The majority of lung cancer cases are diagnosed at the advanced stage of the disease, leading to almost impossible curable surgical resection and poor prognosis. In non-small cell lung cancer (NSCLC), complete surgical resection of stage IA disease could lead to a best prognosis with up to 70% five-year survival rate [2]. Target therapy of lung cancer is applied to patients with advanced lung cancer [3] Target therapy, such as anti-angiogenic therapy in treatment of NSCLC [4] or anti-EGFR therapy [5] has shown to improve survival of patients, but tumor resistance develops quickly in certain cases leading to cancer recurrence. Better understanding of the underlying molecular mechanism of resistance to these target therapies could improve the treatment efficacy to control the advanced lung cancer and prolong survival of patients. Similar to many other cancers, is initiated by activation of oncogenes or inactivation of tumor suppressor genes, such as mutation of K-ras [6] or p53 [7], EGFR amplification [5], COX-2 overexpression [8], or loss of RAR-β expression [9]
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