Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect

Lara, Ester; Mai, Antonello; Calvanese, Vincenzo; Altucci, Lucia; López-Nieva, Pilar; Martínez‐Chantar, María Luz; Varela‐Rey, Marta; Rotili, Dante; Nebbioso, Angela; Ropero, Santiago; Montoya, Guillermo; Oyarzábal, Julen; Llamas‐Velasco, Sara; Serrano, Manuel; Witt, Maike; Villar-Garea, Ana; Inhof, A; Mato, José M.; Esteller, Manel; Fraga, Mario F.

doi:10.1038/onc.2008.436

Cited by 242 publications

(215 citation statements)

References 48 publications

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“…S1; ref. 28), we first investigated the effects of these SIRT inhibitors on the proliferation of the breast carcinoma cell line MCF-7. The natural SIRT inhibitor nicotinamide was also included as a reference compound.…”

Section: Resultsmentioning

confidence: 99%

“…The force field was applied to the SIRT1 and SIRT2 using the in-built CHARMm force field calculation. The binding region for the docking of SIRT2 is the same a previously described (28), which was a 10-Å sphere around the Gln167. The docking region used for SIRT1 was designed in a 10-Åf sphere around the residue of Gln345, which is genetically conserved to the Gln167 of SIRT2.…”

Section: Three-dimension Modelingmentioning

confidence: 99%

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SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Peck

Chen

et al. 2010

Molecular Cancer Therapeutics

383

332

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SIRT proteins play an important role in the survival and drug resistance of tumor cells, especially during chemotherapy. In this study, we investigated the potency, specificity, and cellular targets of three SIRT inhibitors, Sirtinol, Salermide, and EX527. Cell proliferative and cell cycle analyses showed that Sirtinol and Salermide, but not EX527, were effective in inducing cell death at concentrations of 50 μmol/L or over in MCF-7 cells. Instead, EX527 caused cell cycle arrest at G 1 at comparable concentrations. In vitro SIRT assays using a p53 peptide substrate showed that all three compounds are potent SIRT1/2 inhibitors, with EX527 having the highest inhibitory activity for SIRT1. Computational docking analysis showed that Sirtinol and Salermide have high degrees of selectivity for SIRT1/2, whereas EX527 has high specificity for SIRT1 but not SIRT2. Consistently, Sirtinol and Salermide, but not EX527, treatment resulted in the in vivo acetylation of the SIRT1/2 target p53 and SIRT2 target tubulin in MCF-7 cells, suggesting that EX527 is ineffective in inhibiting SIRT2 and that p53 mediates the cytotoxic function of Sirtinol and Salermide. Studies using breast carcinoma cell lines and p53-deficient mouse fibroblasts confirmed that p53 is essential for the Sirtinol and Salermideinduced apoptosis. Further, we showed using small interfering RNA that silencing both SIRTs, but not SIRT1 and SIRT2 individually, can induce cell death in MCF-7 cells. Together, our results identify the specificity and cellular targets of these novel inhibitors and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death. Mol Cancer Ther; 9(4); 844-55. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Three-dimension Modelingmentioning

confidence: 99%

SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2

Peck

Chen

et al. 2010

Molecular Cancer Therapeutics

383

332

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“…To exclude potential off-target effects of the siRNAs, we treated BE(2)-C and MiaPaca-2 cells with the SIRT2-selective inhibitor AC-93253 at 0.6 mM 20 or the SIRT1/ SIRT2 inhibitor Salermide at 50 mM, at which Salermide inhibits SIRT2 but not SIRT1. 21 Real-time RT-PCR and immunoblot analyses showed that treatment with 0.6 mM AC-93253 or 50 mM Salermide considerably reduced N-Myc and c-Myc protein expression, even though 0.6 mM AC-93253 and 50 mM Salermide increased c-Myc mRNA expression (Figures 2a and b).…”

Section: Resultsmentioning

confidence: 99%

“…We next treated BE(2)-C and MiaPaca-2 cells with vehicle control, the SIRT2 inhibitor AC-93253 at 0.8 mM or the SIRT1/SIRT2 inhibitor Salermide at 50 mM, at which Salermide inhibits SIRT2 but not SIRT1. 21 RT-PCR and immunoblot analyses showed that inhibition of SIRT2 deacetylation activity with AC-93253 or Salermide significantly reduced Aurora A mRNA and protein expression (Figures 7b and c). The data suggest that SIRT2 can stabilize Myc protein and exert tumorigenic effects partly through upregulating Aurora A expression.…”

Section: Resultsmentioning

confidence: 99%

“…To exclude potential off-target effects of the siRNAs, we treated BE(2)-C and MiaPaca-2 cells with AC-93253, a small molecule SIRT2-selective deacetylation inhibitor, 20 or the SIRT1/SIRT2 inhibitor Salermide, which inhibits SIRT2 but not SIRT1 at 25-50 mM. 21 Figure S1A). To exclude potential off-target effects of the siRNAs, we treated BE(2)-C and MiaPaca-2 cells with the SIRT2-selective inhibitor AC-93253 at 0.6 mM 20 or the SIRT1/ SIRT2 inhibitor Salermide at 50 mM, at which Salermide inhibits SIRT2 but not SIRT1.…”

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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