Xue Chengyuan, Yu Denise M T, Gherardi Samuele, Koach Jessica, Milazzo Giorgio, Gamble Laura, Liu Bing, Valli Emanuele, Russell Amanda J, London Wendy B, Liu Tao, Cheung Belamy B, Marshall Glenn M, Perini Giovanni, Haber Michelle, Norris Murray D
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Oncotarget. 2016 Aug 23;7(34):54937-54951. doi: 10.18632/oncotarget.10709.
Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease.
MYCN致癌基因是MYC转录调节因子家族的成员之一，其扩增是神经母细胞瘤（儿童期最常见的颅外实体癌）预后不良最有力的预后标志物之一。虽然MYCN已被确认为神经母细胞瘤恶性肿瘤的关键驱动因素，但其潜在的分子机制仍知之甚少。据报道，转录因子激活增强子结合蛋白4（TFAP4）是MYC的直接转录靶点。我们首次表明，原发性神经母细胞瘤患者中TFAP4的高表达与不良临床预后相关。siRNA介导的对表达MYCN的神经母细胞瘤细胞中TFAP4的抑制导致细胞增殖和迁移受到抑制。染色质免疫沉淀试验表明，TFAP4的表达受MYCN的正调控。微阵列分析确定了神经母细胞瘤细胞中受MYCN和TFAP4共同调控的基因，包括参与癌细胞增殖和转移的磷酸核糖焦磷酸合成酶2（PRPS2）和Syndecan-1（SDC1）。总体而言，本研究提示了一种调控回路，即MYCN通过提高TFAP4的表达，与其协同控制一组参与肿瘤进展的特定基因。这些发现突出了在MYCN驱动的神经母细胞瘤中存在MYCN-TFAP4轴，同时也确定了这种侵袭性疾病的潜在治疗靶点。
