SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability

Marshall, Glenn M.; Liu, Pei Y.; Gherardi, Samuele; Scarlett, Christopher J.; Bedalov, Antonio; Xu, Nuo; Iraci, Nunzio; Valli, Emanuele; Ling, Dora; Thomas, Wayne; Bekkum, M. van der Starre-van; Sekyere, Eric; Jankowski, Kacper; Trahair, Toby N.; MacKenzie, Karen L.; Haber, Michelle; Norris, Murray D.; Biankin, Andrew V.; Perini, Giovanni; Liu, Tao

doi:10.1371/journal.pgen.1002135

Cited by 147 publications

(168 citation statements)

References 51 publications

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“…19 Additionally, the pan-SIRT inhibitor nicotinamide suppresses growth of carcinogen-induced mouse and human bladder cancer by reducing the deacetylation activity of SIRT2. 40 Consistent with literature, 41,22,[42][43][44][45] our data suggest that repression of SIRT2 alone or simultaneous repression of SIRT1 and SIRT2 with small molecule inhibitors, such as AC-93253, Salermide, Cambinol, and Tenovin-6, could be an effective strategy for the prevention and therapy of Myc-induced neuroblastoma and pancreatic cancer, and possibly other Myc-induced malignancies.…”

Section: Discussionsupporting

confidence: 89%

“…6,22,24 Our present study shows that SIRT2 represses NEDD4 gene expression in neuroblastoma and pancreatic cells, that SIRT2 binds to NEDD4 gene core promoter and SIRT2 siRNA increases the presence of acetylated histone H4K16 at NEDD4 gene promoter, and that SIRT2 siRNA enhances NEDD4 promoter activity. These data suggest that SIRT2 represses NEDD4 gene transcription by direct binding to NEDD4 gene core promoter region, deacetylating histone H4K16 and, repressing NEDD4 gene promoter activity.…”

Section: Discussionsupporting

confidence: 51%

“…We have previously shown that the proteasome inhibitor MG-132 does not increase Myc protein expression in cancer cells transfected with Myc siRNAs, which ablates Myc mRNA. 22 Here we show that MG-132 significantly increases Myc protein expression in cancer cells transfected with SIRT2 siRNAs, the repression of SIRT2 significantly decreases N-Myc and c-Myc protein half-life, and SIRT2 has no effect on the expression of phosphorylated ERK and GSK3 proteins. We conclude that SIRT2 upregulates Myc protein expression through blocking Myc protein degradation without modulating ERK protein phosphorylation and GSK3 protein expression.…”

Section: Discussionmentioning

confidence: 63%

“…We have previously shown that MG-132 does not increase Myc protein expression in cells transfected with Myc siRNAs, which ablates Myc mRNA. 22 As shown in Figure 2c, MG-132 significantly upregulated N-Myc and c-Myc protein expression in BE(2)-C and MiaPaca-2 cells transfected with SIRT2 siRNA-1 or SIRT2 siRNA-2 for 48 h. We next treated the cells with 50 mM cycloheximide at different time points after transfection with control siRNA or SIRT2 siRNA-1 for only 30 h, when the effect of SIRT2 siRNA-1 on Myc protein expression was minimal. Immunoblot analysis showed that N-Myc protein half-life was reduced from B50 min in BE(2)-C cells transfected with control siRNA to B32 min in BE(2)-C cells transfected with SIRT2 siRNA-1 (Figure 2d).…”

Section: Resultsmentioning

confidence: 99%

“…6,22,24 We therefore performed chromatin immunoprecipitation (ChIP) assays with an anti-SIRT2 antibody (Ab), an anti-acetylated histone H4 lysine 16 (acetyl H4K16) Ab or a control Ab and PCR with primers targeting upstream control region or core promoter region of the NEDD4 gene promoter. The ChIP assays showed that the anti-SIRT2 and the anti-acetyl H4K16 antibodies efficiently immunoprecipitated the region of NEDD4 gene core promoter (Figure 4d).…”

Section: Resultsmentioning

confidence: 99%

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The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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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. The Myc family of oncoproteins are commonly upregulated in human cancer. MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression occur in 20-25% of neuroblastoma and correlate with a poor patient outcome. 1-3 MYC oncogene amplification occurs in 54% of human pancreatic cancer cell lines 4 and 33% of human primary pancreatic tumors, 5 and significant c-Myc oncoprotein overexpression is seen in B50% of human primary pancreatic tumors. 6 Stabilization and degradation of Myc oncoproteins are controlled by ordered phosphorylation at serine 62 (S62) and threonine 58 (T58) and consequent ubiquitinproteasome pathway-mediated proteolysis. 7-9 Aurora A interacts with both N-Myc and ubiquitin, and blocks ubiquitin-regulated N-Myc protein degradation. 8 Myc oncoproteins induce malignant transformation by binding to cognate DNA sequences and consequently modulating gene transcription 10-13 as well as by enhancing ribosome biogenesis and consequently upregulating protein expression, 14,15 leading to cell proliferation.Recruitment of histone deacetylase (HDACs) to gene promoters induces histone hypoacetylation and transcriptional repression, particularly of tumor suppressor genes. 16 In a comprehensive panel of normal cells, cancer cell lines, normal tissues, and primary tumors, global loss of monoacetylation of histone H4 at lysine 16 (H4K16) is seen only in cancer cells and is associated with early stages of tumorigenesis. 17 One of the HDACs that cause H4K16 deacetylation is the class III HDAC SIRT2, which shows a strong preference for acetylated H4K16. 18 Mo...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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Sirtuins as Drug Targets

Zwergel

Rotili

Mai

2019

Epigenetic Drug Discovery

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CCNB1IP1 prevents ubiquitination‐mediated destabilization of MYCN and potentiates tumourigenesis of MYCN‐amplificated neuroblastoma

Zhou

Yan

Zhou

et al. 2023

Clinical & Translational Med

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Background MYCN amplification as a common genetic alteration that correlates with a poor prognosis for neuroblastoma (NB) patients. However, given the challenge of directly targeting MYCN, indirect strategies to modulate MYCN by interfering with its cofactors are attractive in NB treatment. Although cyclin B1 interacting protein 1 (CCNB1IP1) has been found to be upregulated in MYCN‐driven mouse NB tissues, its regulation with MYCN and collaboration in driving the biological behaviour of NB remains unknown. Methods To evaluate the expression and clinical significance of CCNB1IP1 in NB patients, public datasets, clinical NB samples and cell lines were explored. MTT, EdU incorporation, colony and tumour sphere formation assays, and a mouse xenograft tumour model were utilized to examine the biological function of CCNB1IP1. The reciprocal manipulation of CCNB1IP1 and MYCN and the underlying mechanisms involved were investigated by gain‐ and loss‐of‐function approaches, dual‐luciferase assay, chromatin immunoprecipitation (CHIP) and co‐immunoprecipitation (Co‐IP) experiments. Results CCNB1IP1 was upregulated in MYCN‐amplified (MYCN‐AM) NB cell lines and patients‐derived tumour tissues, which was associated with poor prognosis. Phenotypic studies revealed that CCNB1IP1 facilitated the proliferation and tumourigenicity of NB cells in cooperation with MYCN in vitro and in vivo. Mechanistically, MYCN directly mediates the transcription of CCNB1IP1, which in turn attenuated the ubiquitination and degradation of MYCN protein, thus enhancing CCNB1IP1‐MYCN cooperativity. Moreover, CCNB1IP1 competed with F box/WD‐40 domain protein 7 (FBXW7) for MYCN binding and enabled MYCN‐mediated tumourigenesis in a C‐terminal domain‐dependent manner. Conclusions Our study revealed a previously uncharacterized mechanism of CCNB1IP1‐mediated MYCN protein stability and will provide new prospects for precise treatment of MYCN‐AM NB based on MYCN‐CCNB1IP1 interaction.

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SIRT1 Promotes N-Myc Oncogenesis through a Positive Feedback Loop Involving the Effects of MKP3 and ERK on N-Myc Protein Stability

Cited by 147 publications

References 51 publications

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

Sirtuins as Drug Targets

CCNB1IP1 prevents ubiquitination‐mediated destabilization of MYCN and potentiates tumourigenesis of MYCN‐amplificated neuroblastoma

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