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A Novel Sirtuin 2 (SIRT2) Inhibitor with P53-Dependent Pro-Apoptotic

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A Novel Sirtuin 2 (SIRT2) Inhibitor with P53-Dependent Pro-Apoptotic THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 289, NO. 8, pp. 5208–5216, February 21, 2014 © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer*□S Received for publication, August 19, 2013, and in revised form, December 17, 2013 Published, JBC Papers in Press, December 30, 2013, DOI 10.1074/jbc.M113.487736 Gesine Hoffmann‡**, Frank Breitenbücher§, Martin Schuler§¶, and Ann E. Ehrenhofer-Murray‡**1 From the ‡Zentrum fu¨r Medizinische Biotechnologie, Universität Duisburg-Essen, 45117 Essen, Germany, the §Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum, Universitätsklinikum Essen, 45147 Essen, Germany, the ¶German Cancer Consortium (DKTK) , 69120 Heidelberg, Germany, and the **Humboldt-Universität zu Berlin, Institut fu¨r Biologie, Abteilung Molekulare Zellbiologie, 10115 Berlin, Germany Background: Pharmacological inhibition of the NADϩ-dependent deacetylase SIRT2 holds promise for cancer therapy by preventing deacetylation and inactivation of p53. Results: We identified two novel SIRT2 inhibitors that induce apoptosis in a p53-dependent fashion and activate three p53 target genes. Conclusion: Small-molecule inhibition of SIRT2 activates p53-dependent apoptosis in cancer cells. Significance: The compounds reported here are promising lead candidates for use in cancer treatment. ؉ Sirtuin 2 (SIRT2) is an NAD -dependent protein deacetylase activity (3–5). Sirtuin enzymes have received widespread atten- whose targets include histone H4 lysine 16, p53, and ␣-tubulin. tion over the last few years due to their diverse physiological Because deacetylation of p53 regulates its effect on apoptosis, roles in metabolism, aging, and age-related human disorders pharmacological inhibition of SIRT2-dependent p53 deacetyla- (6–8). SIRT2 is the closest homolog to Hst2 from S. cerevisiae, tion is of great therapeutic interest for the treatment of cancer. which is a cytoplasmic H4 lysine 16 (H4 K16) histone deacety- Here, we have identified two structurally related compounds, lase that disrupts telomeric silencing and increases rDNA AEM1 and AEM2, which are selective inhibitors of SIRT2 (IC50 silencing upon overexpression (9, 10). SIRT2 deacetylates ⑀-N- values of 18.5 and 3.8 ␮M, respectively), but show only weak acetyllysine residues on a variety of protein substrates (11), effects on other sirtuins such as SIRT1, SIRT3, and yeast Sir2. including histones H3 (12) and H4 (13), the transcription fac- Interestingly, both compounds sensitized non-small cell lung tors p53 (14), p65 (15), Foxo1 (16), and Foxo3a (17), as well as cancer cell lines toward the induction of apoptosis by the DNA- ␣-tubulin (18) (for review, see Ref. 19). Unlike other sirtuins, damaging agent etoposide. Importantly, this sensitization was SIRT2 is mainly cytoplasmic, where it co-localizes with and dependent on the presence of functional p53, thus establishing a ␣ deacetylates lysine 40 of -tubulin (18). During G2/M phase, link between SIRT2 inhibition by these compounds and p53 SIRT2 relocates to the nucleus and deacetylates histone H4 K16 activation. Further, treatment with AEM1 and AEM2 led to ele- (13, 20), thereby modulating chromatin condensation during vated levels of p53 acetylation and to increased expression of metaphase (13, 21). SIRT2 levels increase in mitosis, and SIRT2 WAF1 CDKN1A, which encodes the cell cycle regulator p21 ,as overexpression prolongs M phase and delays mitotic exit (21), well as the pro-apoptotic genes PUMA and NOXA, three transcrip- thus demonstrating a role for SIRT2 in cell cycle regulation tional targets of p53. Altogether, our data suggest that inhibition of (22). In mice, the absence of SIRT2 leads to reduced activity of SIRT2 by these compounds causes increased activation of p53 by the anaphase-promoting complex/cyclosome through deacety- decreasing SIRT2-dependent p53 deacetylation. These com- lation of Cdh1 and Cdc20, which causes higher rates of aneu- pounds thus provide a good opportunity for lead optimization and ploidy. Consequently, SIRT2-deficient mice show an increased drug development to target p53-proficient cancers. cancer incidence, suggesting that SIRT2 is a tumor suppressor. However, as for other sirtuins (23), conflicting data exist regarding the role of SIRT2 in carcinogenesis. In contrast to its 2 Sirtuin 2 (SIRT2) is one of seven members of the sirtuin role as a potential tumor suppressor, SIRT2 deacetylates and family of proteins, whose members are homologous to the thus inhibits the activity of p53 (14, 24), suggesting that SIRT2 silencing protein Sir2 from Saccharomyces cerevisiae (1, 2) and ϩ inhibition may be useful for anticancer treatment. An efficient possess NAD -dependent histone and protein deacetylase increase of in vivo acetylation of p53 in a breast carcinoma cell line requires inhibition of both SIRT2 and its homolog SIRT1 * This work was supported by Deutsche Forschungsgemeinschaft Graduate (14), which also deacetylates p53 (25). Consequently, simulta- Research Training Program Grants GRK1431 (to A. E.-M.) and SCHU1541/ neous inhibition of both SIRT1 and SIRT2 induces apoptosis in 5-1 (to M. S.) and by the University of Duisburg-Essen. some tumor cell lines and in Burkitt lymphoma xenografts (14, □S This article contains supplemental Figs. S1 and S2. 1 To whom correspondence should be addressed: Humboldt-Universität zu 26). In other cell lines, SIRT2 down-regulation alone is suffi- Berlin, Abteilung Molekulare Zellbiologie, Chausseestr. 117, D-10115 Ber- cient to cause apoptosis, and SIRT2 depletion leads to p53 accu- lin, Germany. Tel.: 49-30-2093-8137; Fax: 49-30-2093-8127; E-mail: ann. mulation by causing activation of the p38 MAP kinase, which [email protected]. 2 The abbreviations used are: SIRT2, sirtuin 2; MAL, Boc(Ac)Lys-7-amino-4-meth- leads to degradation of p300 and subsequent degradation of the yl-coumarin; NSCLC, non-small cell lung cancer; TM, tamoxifen mutant. negative p53 regulator MDM2 (27). Furthermore, another 5208 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 289•NUMBER 8•FEBRUARY 21, 2014 p53-dependent Apoptosis by a SIRT2 Inhibitor study reported increased SIRT2 expression in 6 of 11 human to initiate the reaction, which was incubated at 37 °C for 4 h. pancreatic adenocarcinomas (28), and SIRT2 was found to be This allowed for ϳ50% deacetylation of MAL. After incubation, up-regulated in human breast cancer and hepatocellular carci- 20 ␮l of trypsin solution (0.5 mg/ml) was added, and the trypsin noma (29). Altogether, the role of SIRT2 as an oncogene or a cleavage reaction was allowed to proceed at 37 °C for 1 h. Fluo- tumor suppressor may therefore vary depending on the cancer rescence readings were obtained using a fluorescence reader type and requires further investigation to develop SIRT2 inhib- (GENiosPro TECAN), with the excitation wavelength set to 360 itors as therapeutic interventions for the treatment of selected nm and the emission set to 465 nm. IC50 values and curve fitting cancer types. were performed using GraphPad Prism 5.04 with nonlinear Next to its role as an anticancer target, SIRT2 also holds regression analysis. The indicated values are the average of promise as a target for the treatment of neurodegenerative dis- three replicates. orders in that SIRT2 inhibition in primary neuronal and inver- Potential autofluorescence of the compounds, which may tebrate models of Parkinson and Huntington diseases rescues confound the deacetylation assay, was controlled by measuring neurotoxicity induced by ␣-synuclein and huntingtin proteins, the fluorescence of reaction mixtures containing all compo- respectively (30–32). nents except the sirtuin enzyme with or without 250 ␮M com- So far, only few inhibitors of SIRT2 have been identified, but pounds. None of the compounds presented here showed auto- they lack selectivity for SIRT2 versus other sirtuins or have sub- fluorescence (data not shown). A potential effect of the optimal pharmacological properties (see “Discussion”). In this compounds on the trypsin cleavage reaction was investigated study, we report the identification of two novel, structurally by testing the ability of the compounds to inhibit trypsin cleav- related SIRT2 inhibitors, compounds AEM1 and AEM2. They age of unacetylated MAL. No compound inhibition was show selective inhibition of SIRT2 with IC50 values of 18.5 and observed (data not shown). The MAL deacetylation assay was 3.8 ␮M, respectively, but no inhibition of the related sirtuins used to screen a library of ϳ18,000 compounds (ChemBioNet, SIRT1, SIRT3, and yeast Sir2. Treatment of cancer cell lines Screening Unit of the Leibniz-Institute for Molecular Pharma- with these compounds caused sensitization of the cells to eto- cology, Berlin, Germany) for SIRT1 inhibitors.3 poside-induced apoptosis. Furthermore, we show that the sen- HPLC-based p53 Peptide Deacetylation Assay—A deacetyla- sitization by compound AEM2 partially depends on the pres- tion assay using a p53 peptide substrate lacking a fluorophore ence of functional p53. Furthermore, AEM1 and AEM2 caused was performed as follows. Assay conditions were as for the increased acetylation of p53 and enhanced the induction of the MAL deacetylation assay, but with a reaction volume of 50 ␮l. canonical p53 target genes CDKN1A, PUMA, and NOXA. Thus, After preincubation of SIRT2 or SIRT1 with the inhibitors for AEM2 constitutes a promising lead compound for the develop- 10 min, the
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