含有前列腺癌风险性SNPrs1741708的潜在增强子座位在前列腺癌中功能与机制的研究

Molecular Mechanism and Functional Study of Enhancer Containing Risk SNP rs1741708 in Prostate Cancer Cell

前列腺癌(Prostate Cancer,PCa)是老年男性最常见的恶性肿瘤之一.全基因组关联研究(Genome wide Association Studies,GWAS)发现SNP(Single Nucleotide Polymorphism)位点rs1741708与前列腺癌高风险性相关.表观遗传学标志物和荧光素酶报告子研究证实含有该风险性位点的染色体区段是等位基因特异性的增强子元件.敲除风险性增强子会导致细胞迁移能力减弱.利用Capture-C揭示该增强子在全基因组范围内的互作基因座位,结合风险性增强子敲除后基因表达的改变,鉴定出一些该增强子的直接靶基因.初步的Rescue研究发现,在敲除细胞中过表达靶基因IKZF3后,细胞迁移能力得到部分恢复,提示IKZF3是含有SNP rs1741708的风险性增强子影响肿瘤恶性进展的下游靶基因之一.

Prostate cancer(PCa) is one of the most common malignant tumors in older men. Genome wide association studies(GWAS) found that the SNP(single nucleotide polymorphism) rs1741708 is associated with high risk of prostate cancer. Epigenetics and luciferase reporter study confirmed that chromosome segment containing this risk SNP is an allele-specific enhancer element. Knockout the risk enhancers resulted in reduced cell migration. Capture-C assay captured the interaction locus with the enhancer, and we identified some of the direct target genes whose m RNA levels are down-regulated dramatically after deletion of the risk enhancer element. Rescue study found that overexpressing the target gene IKZF3 in enhancer–deleted homozygotes, the cell migration ability could be partially restored, suggesting that IKZF3 is one of the downstream target genes of the risk enhancer containing SNP rs1741708 affecting the malignant progression of the tumor.