Abstract:
MDS1 and EVI1 complex locus (MECOM), a transcription factor encoding several variants, has been implicated in progression of ovarian cancer. The function of regulatory regions in regulating MECOM expression in ovarian cancer is not fully understood. In this study, MECOM expression was evaluated in ovarian cancer cell lines treated with bromodomain and extraterminal (BET) inhibitor JQ-1. Oncogenic phenotypes were assayed using assays of CCK-8, colony formation, wound-healing and transwell. Oncogenic phenotypes were estimated in stable sgRNA-transfected OVCAR3 cell lines. Xenograft mouse model was assayed via subcutaneous injection of enhancer-deleted OVCAR3 cell lines. The results displayed that expression of MECOM is downregulated in cell lines treated with JQ-1. Data from published ChIP-sequencing (H3K27Ac) in 3 ovarian cancer cell lines displayed a potential enhancer around the first exon. mRNA and protein expression were downregulated in OVCAR3 cells after deletion of the MECOM enhancer. Similarly, oncogenic phenotypes both in cells and in the xenograft mouse model were significantly attenuated. This study demonstrates that JQ-1 can inhibit the expression of MECOM and tumorigenesis. Deletion of the enhancer activity of MECOM has an indispensable role in inhibiting ovarian cancer progress, which sheds light on a promising opportunity for ovarian cancer treatment through the application of this non-coding DNA deletion.
摘要:
MDS1和EVI1复合基因座(MECOM),编码几种变体的转录因子,与卵巢癌的进展有关。调节区在卵巢癌中调节MECOM表达的功能尚不完全清楚。在这项研究中,在用溴结构域和外端(BET)抑制剂JQ-1处理的卵巢癌细胞系中评估MECOM表达。使用CCK-8、集落形成、伤口愈合和Transwell。在稳定的sgRNA转染的OVCAR3细胞系中估计致癌表型。通过皮下注射增强子缺失的OVCAR3细胞系来测定异种移植小鼠模型。结果显示MECOM的表达在用JQ-1处理的细胞系中下调。来自3种卵巢癌细胞系中公开的ChIP测序(H3K27Ac)的数据在第一外显子周围显示出潜在的增强子。MECOM增强子缺失后,OVCAR3细胞的mRNA和蛋白表达下调。同样,细胞和异种移植小鼠模型中的致癌表型均显着减弱。本研究表明JQ-1可以抑制MECOM的表达和肿瘤发生。MECOM增强子活性的缺失在抑制卵巢癌进展中具有不可或缺的作用,通过应用这种非编码DNA缺失,这为卵巢癌治疗提供了有希望的机会。