ZCCHC10通过激活P53促进急性髓系白血病细胞中CCL18基因的转录

ZCCHC10 Promotes Transcription of CCL18 Gene by Activating P53 in Acute Myeloid Leukemia Cells

肿瘤抑制因子P53是一种转录因子,可激活一系列靶基因的转录,从而调控细胞周期停滞、DNA修复、免疫、炎症和细胞凋亡等多种生理或病理过程。前期研究表明,CCHC型锌指蛋白10(zinc finger CCHC-type containing 10,ZCCHC10)通过激活P53在肺癌和急性髓系白血病中发挥抑癌作用。为进一步探讨ZCCHC10在急性髓系白血病中的作用机制,本文通过RNA测序(RNA sequencing,RNA-seq)技术对过表达ZCCHC10或空载体的ML2细胞进行了转录组分析,一共鉴定到1284个差异基因[|log2(fold change)|逸1,q值约0.05],包括778个上调基因和506个下调基因。其中,趋化因子CCL18在过表达ZCCHC10的ML2细胞中上调18倍。生物信息学分析显示,CCL18基因启动子上含有两个P53反应元件。生物素标记DNA亲和实验和染色质免疫共沉淀实验证实,P53可结合到CCL18基因启动子上。荧光素酶活性分析表明,P53可以增强CCL18基因启动子的活性。这些研究表明ZCCHC10通过激活P53促进CCL18基因的表达。

The tumor suppressor P53 is a transcription factor that activates transcription of a number of target genes to regulate cell cycle arrest,DNA repair,immunity,inflammation,and apoptosis.Our previous study showed that zinc finger CCHC-type containing 10(ZCCHC10)plays an anti-oncogenic role through activat-ing P53 in lung cancer and acute myeloid leukemia.To further investigate the mechanism of ZCCHC10 in acute myeloid leukemia,transcriptome analysis of ML2 cells overexpressing ZCCHC10 gene or empty vector was performed by RNA sequencing(RNA-seq),and a total of 1284 differentially expressed genes were identified[log2(fold change)≥1,q value<0.05],including 778 upregulated genes and 506 downregulated genes.The chemokine CCL18 was significantly upregulated(18-fold)in ZCCHC10-overexpressing ML2 cells.Bioinformatics analysis revealed that the CCL18 gene promoter contains two P53 response elements.Biotin-labeled DNA affinity assay and chromatin immunoprecipitation(ChIP)assay confirmed the binding of P53 to the CCL18 promoter.Luciferase activity analysis showed that P53 enhanced CCL18 promoter activity.The study suggests that ZCCHC10 promotes CCL18 gene expression through activating P53.