Department of Pediatrics, The Second Xiangya Hospital, Central South University, PR China.
Department of Pediatrics, The Second Xiangya Hospital, Central South University, PR China.
Biochem Biophys Res Commun. 2019 Mar 26;511(1):35-40. doi: 10.1016/j.bbrc.2019.01.087. Epub 2019 Feb 11.
The MYCN oncoprotein induces the proliferation of neuroblastoma cells through regulating gene transcription. The E2F transcription factor 5 (E2F5) plays an oncogenic role in several types of cancer, however, its role in neuroblastoma cells remains poorly characterized. We report here that MYCN positively regulates E2F5 expression in neuroblastoma cells. Analyses of chromatin immunoprecipitation (ChIP) and reporter gene assay demonstrate that MYCN directly binds to a Myc E-Box DNA binding motif within the promoter of E2F5 gene, whereby inducing its transcription. In addition, E2F5 knockdown inhibits the proliferation of MYCN-amplified neuroblastoma cells. Furthermore, E2F5 knockdown inhibits cell cycle progression, which could be attributed to its regulation in the expression of related cyclin-dependent kinases (CDKs), including CDK2 and CDK6. These results suggest that MYCN-regulated E2F5 upregulation is an important mechanism through which MYCN induces the proliferation of neuroblastoma cells. In conclusion, this study identifies E2F5 as a pro-proliferative factor in MYCN-amplified neuroblastoma cells, and also implicates it as a potential target in neuroblastoma treatment.
MYCN 癌蛋白通过调节基因转录诱导神经母细胞瘤细胞的增殖。E2F 转录因子 5（E2F5）在几种类型的癌症中发挥致癌作用，然而，其在神经母细胞瘤细胞中的作用仍知之甚少。我们在这里报告 MYCN 可正向调节神经母细胞瘤细胞中 E2F5 的表达。染色质免疫沉淀（ChIP）和报告基因分析表明，MYCN 可直接结合 E2F5 基因启动子内的 Myc E-Box DNA 结合基序，从而诱导其转录。此外，E2F5 敲低抑制 MYCN 扩增的神经母细胞瘤细胞的增殖。此外，E2F5 敲低抑制细胞周期进程，这可能归因于其对相关细胞周期蛋白依赖性激酶（CDKs），包括 CDK2 和 CDK6 的表达的调节。这些结果表明，MYCN 调节的 E2F5 上调是 MYCN 诱导神经母细胞瘤细胞增殖的重要机制。总之，本研究鉴定出 E2F5 是 MYCN 扩增型神经母细胞瘤细胞中的促增殖因子，并暗示其可能是神经母细胞瘤治疗的潜在靶点。
