Discovery, In Vivo Activity, and Mechanism of Action of a Small-Molecule p53 Activator

Laı́n, Sonia; Hollick, Jonathan J.; Campbell, Johanna; Staples, Oliver; Higgins, Maureen; Aoubala, Mustapha; McCarthy, Anna R.; Appleyard, Virginia; Murray, Kermit K.; Baker, Lee D.; Thompson, Alastair; Mathers, Joanne; Holland, Stephen J.; Stark, Michael J. R.; Pass, Georgia J.; Woods, Julie A.; Lane, David P.; Westwood, Nicholas J.

doi:10.1016/j.ccr.2008.03.004

Cited by 464 publications

(520 citation statements)

References 50 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: 88%

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: 88%

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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“…In contrast, NAMPT knockdown significantly reduced FOXO3a expression in PC3 cells (Figure 8d). Similar effect was seen with treatment of NAMPT inhibitor FK866, but not SIRT1 inhibitor tenovin-6 (Lain et al, 2008) (Figure 8e). Interestingly, NAMPT inhibition did not change FOXO3a RNA level, but FOXO3a Figure 9), indicating likely the involvement of NAD þ -dependent posttranslational regulation of FOXO3a protein stability.…”

Section: Nampt Is Overexpressed In Human Prostate Cancersupporting

confidence: 75%

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD þ ) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD þ -dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H 2 O 2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

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“…10,11 Tenovin-1 is not a specific inhibitor of SIRT1, as it also inhibits other Sirtuins with an IC 50 value of 21 mM for SIRT1, 10 mM for SIRT2, and 67 mM for SIRT3. 12 In our previous study, we used doses of Tenovin-1 up to 25 mM, which would affect SIRT1 and/or SIRT2.…”

Section: Introductionmentioning

confidence: 99%

Sirtuin deacetylases: A new target for melanoma management

et al. 2014

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y These authors contributed equally to this work.M elanoma continues to cause more deaths than any other skin cancer, necessitating the development of new avenues of treatment. One promising new opportunity comes in the form of mechanism-based therapeutic targets. We recently reported the overexpression and delocalization of the class III histone deacetylase SIRT1 in melanoma, and demonstrated that its small molecule inhibition via Tenovin-1 decreased cell growth and viability of melanoma cells, possibly by a p53 mediated induction of p21. Here, we support our data using additional SIRT inhibitors, viz. Sirtinol and Ex-527, which suggests possible benefits of concomitantly inhibiting more than one Sirtuin for an effective cancer management strategy. This "Extra View" paper also includes a discussion of our results in the context of similar recent and concurrent studies. Furthermore, we expand upon our findings in an analysis of new research that may link the cellular localization and growth effects of SIRT1 with the PI3K signaling pathway.

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Discovery, In Vivo Activity, and Mechanism of Action of a Small-Molecule p53 Activator

Cited by 464 publications

References 50 publications

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

Sirtuin deacetylases: A new target for melanoma management

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