title: The histone deacetylase SIRT2 stabilizes Myc oncoproteins.
abstract: Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, Sydney, NSW 2031, Australia.
authors.forename: P Y
authors.initials: PY
authors.lastname: Liu
authors.forename: N
authors.initials: N
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Malyukova
authors.forename: C J
authors.initials: CJ
authors.lastname: Scarlett
authors.forename: Y T
authors.initials: YT
authors.lastname: Sun
authors.forename: X D
authors.initials: XD
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Ling
authors.forename: S-P
authors.initials: SP
authors.lastname: Su
authors.forename: C
authors.initials: C
authors.lastname: Nelson
authors.forename: D K
authors.initials: DK
authors.lastname: Chang
authors.forename: J
authors.initials: J
authors.lastname: Koach
authors.forename: A E
authors.initials: AE
authors.lastname: Tee
authors.forename: M
authors.initials: M
authors.lastname: Haber
authors.forename: M D
authors.initials: MD
authors.lastname: Norris
authors.forename: C
authors.initials: C
authors.lastname: Toon
authors.forename: I
authors.initials: I
authors.lastname: Rooman
authors.forename: C
authors.initials: C
authors.lastname: Xue
authors.forename: B B
authors.initials: BB
authors.lastname: Cheung
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: G M
authors.initials: GM
authors.lastname: Marshall
authors.forename: A V
authors.initials: AV
authors.lastname: Biankin
authors.forename: T
authors.initials: T
authors.lastname: Liu
mesh_terms: D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056827:Endosomal Sorting Complexes Required for Transport; D015870:Gene Expression; D006801:Humans; D009284:Naphthols / Q000494:pharmacology; D000075702:Nedd4 Ubiquitin Protein Ligases; D010666:Phenylpropionates / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; C539427:N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide; D009284:Naphthols; D010666:Phenylpropionates; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C474199:SIRT2 protein, human; D056565:Sirtuin 2