SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability

The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc–induced neuroblastoma.

N-Myc癌蛋白（N-Myc oncoprotein）是神经母细胞瘤（neuroblastoma）肿瘤发生过程中的关键调控因子，其功能行使尚需额外调控机制介导，以实现N-Myc表达由低水平向高水平的转变。当磷酸化ERK蛋白（ERK）介导N-Myc蛋白在丝氨酸62（Serine 62）位点发生磷酸化时，N-Myc蛋白的稳定性会显著提升。本研究报道了一条全新的正向反馈环路：N-Myc可直接诱导III类组蛋白去乙酰化酶SIRT1（class III histone deacetylase SIRT1）的转录，而SIRT1随后又可增强N-Myc蛋白的稳定性。SIRT1可结合N-Myc蛋白的Myc Box I结构域，并在丝裂原活化蛋白激酶磷酸酶3（mitogen-activated protein kinase phosphatase 3, MKP3）的基因启动子区域形成新型转录抑制复合物，最终引发MKP3转录抑制、ERK蛋白磷酸化、N-Myc蛋白在丝氨酸62位点的磷酸化以及N-Myc蛋白稳定性提升。值得注意的是，在癌前细胞中，SIRT1的表达会上调而MKP3的表达则会下调；使用SIRT1抑制剂坎比诺尔（Cambinol）进行预防性治疗，可降低TH-MYCN转基因小鼠（TH-MYCN transgenic mice）的肿瘤发生风险。本研究数据证实了SIRT1在N-Myc介导的肿瘤发生过程中的关键作用，以及SIRT1抑制剂在预防和治疗N-Myc诱导的神经母细胞瘤中的应用价值。