The histone deacetylase SIRT2 stabilizes Myc oncoproteins

Liu, P. Y.; Xu, N.; Koach, J.; Tee, A. E.; Haber, M.; Norris, M. D.; Toon, C.; Rooman, I.; Xue, C.; Cheung, B. B.; Kumar, S.; Marshall, G. M.; Malyukova, A.; Biankin, A. V.; Liu, T.; Scarlett, C. J.; Sun, Y. T.; Zhang, X. D.; Ling, D.; Su, S.-P.; Nelson, C.; Chang, D. K.

Title: The histone deacetylase SIRT2 stabilizes Myc oncoproteins
Creator: Liu, P. Y.; Xu, N.; Koach, J.; Tee, A. E.; Haber, M.; Norris, M. D.; Toon, C.; Rooman, I.; Xue, C.; Cheung, B. B.; Kumar, S.; Marshall, G. M.; Malyukova, A.; Biankin, A. V.; Liu, T.; Scarlett, C. J.; Sun, Y. T.; Zhang, X. D.; Ling, D.; Su, S.-P.; Nelson, C.; Chang, D. K.
Relation: Cell Death & Differentiation Vol. 20, Issue 3, p. 503-514
Publisher Link: http://dx.doi.org/10.1038/cdd.2012.147
Publisher: Nature Publishing Group
Resource Type: journal article
Date: 2013
Description: 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.
Subject: neuroblastoma; pancreatic cancer; N-Myc; histone deacetylase; SIRT2; NEDD4
Identifier: http://hdl.handle.net/1959.13/1300702
Identifier: uon:20120
Identifier: ISSN:1350-9047
Language: eng
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