SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability

PLoS Genet. 2011 Jun;7(6):e1002135. doi: 10.1371/journal.pgen.1002135.

Glenn M Marshall ¹, Pei Y Liu, Samuele Gherardi, Christopher J Scarlett, Antonio Bedalov, Ning Xu, Nuncio Iraci, Emanuele Valli, Dora Ling, Wayne Thomas, Margo van Bekkum, Eric Sekyere, Kacper Jankowski, Toby Trahair, Karen L Mackenzie, Michelle Haber, Murray D Norris, Andrew V Biankin, Giovanni Perini, Tao Liu

Affiliations

Affiliation

1 Children's Cancer Institute Australia for Medical Research, Randwick, Australia.

PMID: 21698133 DOI: 10.1371/journal.pgen.1002135

Abstract

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.

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