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

Publication Type:

Journal Article

Authors:

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

Source:

PLoS genetics, Volume 7, Issue 6, p.e1002135 (2011)

Keywords:

2011, Clinical Research Division

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.