title: A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer.
abstract: Sirtuin 2 (SIRT2) is an NAD(+)-dependent protein deacetylase whose targets include histone H4 lysine 16, p53, and α-tubulin. Because deacetylation of p53 regulates its effect on apoptosis, pharmacological inhibition of SIRT2-dependent p53 deacetylation is of great therapeutic interest for the treatment of cancer. Here, we have identified two structurally related compounds, AEM1 and AEM2, which are selective inhibitors of SIRT2 (IC50 values of 18.5 and 3.8 μM, respectively), but show only weak effects on other sirtuins such as SIRT1, SIRT3, and yeast Sir2. Interestingly, both compounds sensitized non-small cell lung cancer cell lines toward the induction of apoptosis by the DNA-damaging agent etoposide. Importantly, this sensitization was dependent on the presence of functional p53, thus establishing a link between SIRT2 inhibition by these compounds and p53 activation. Further, treatment with AEM1 and AEM2 led to elevated levels of p53 acetylation and to increased expression of CDKN1A, which encodes the cell cycle regulator p21(WAF1), as well as the pro-apoptotic genes PUMA and NOXA, three transcriptional targets of p53. Altogether, our data suggest that inhibition of SIRT2 by these compounds causes increased activation of p53 by decreasing SIRT2-dependent p53 deacetylation. These compounds thus provide a good opportunity for lead optimization and drug development to target p53-proficient cancers.
authors.affiliation: From the Zentrum für Medizinische Biotechnologie, Universität Duisburg-Essen, 45117 Essen, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Hoffmann
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbücher
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Ann E
authors.initials: AE
authors.lastname: Ehrenhofer-Murray
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D056565:Sirtuin 2
keywords: Cancer Biology; Histone Deacetylase Inhibitors; SIRT; Sirt1; Sirt2; Sirtuins; p53