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 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 mitogenactivated 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, SIRT 1 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 SIRT 1 in N-Myc oncogenesis and SIRT 1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma.