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.
|Authors||Marshall, G.M.; Liu, P.; Gherardi, S.; Scarlett, C.; Bedalov, A.; Xu, N.; Iraci, N.; Valli, E.; Ling, D.; Thomas, W.; Van Bekkum, M.; Sekyere, E.; Jankowski, K.; Trahair, T.; MacKenzie, K.L.; Haber, M.; Norris, M.; Biankin, A.V.; Perini, G.; Liu, T.|
|Publisher Name||PLOS GENET|
|DOI||10.1371/journal.pgen.1002135 PGENETICS-D-10-00535 [pii]|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21698133|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11050|