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 mechanismsconverting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 byphosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced thetranscription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to MycBox I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activatedprotein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Mycprotein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 downregulated,in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis inTH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors inthe prevention and therapy of N-Myc–induced neuroblastoma.