Abstract
Sirtuins are NAD+ dependent deacetylases and/or ADP-ribosyl transferases active on histone and non-histone substrates. The first sirtuin was discovered as a transcriptional repressor of the mating-type-loci (Silent Information Regulator sir2) in the budding yeast, where it was shown to extend yeast lifespan. Seven mammalian sirtuins (SIRT1-7) have been now identified with distinct subcellular localization, enzymatic activities and substrates. These enzymes regulate cellular processes such as metabolism, cell survival, differentiation, DNA repair and they are implicated in the pathogenesis of solid tumors and leukemias. The purpose of the present study was to investigate the role of sirtuin expression, activity and inhibition in the survival of pediatric sarcoma cell lines.We have analyzed the expression of SIRT1 and SIRT2 in a series of pediatric sarcoma tumor cell lines and normal cells, and we have evaluated the activity of the sirtuin inhibitor and p53 activator tenovin-6 (Tv6) in synovial sarcoma and rhabdomyosarcoma cell lines. We show that SIRT1 is overexpressed in synovial sarcoma biopsies and cell lines in comparison with normal mesenchymal cells. Tv6 induced apoptosis as well as impaired autophagy flux. Using siRNA to knock down SIRT1 and SIRT2, we show that the expression of both proteins is crucial for the survival of rhabdomyosarcoma cells and that the loss of SIRT1 expression results in a decreased LC3II expression. Our results show that SIRT1 and SIRT2 expressions are crucial for the survival of synovial sarcomas and rhabdomyosarcomas, and demonstrate that the pharmacological inhibition of sirtuins impairs the autophagy process and induces tumor cell death.
Highlights
Seven sirtuins (SIRT1-7) have been identified in mammals, all of them sharing the NAD+ binding and catalytic domain, but targeting different substrates and distinct but not exclusive subcellular localizations
We have investigated the expression and activity of SIRT1 and SIRT2 in synovial sarcomas and rhabdomyosarcomas, and we evaluated the effects of sirtuin modulation with the small-molecule tenovin-6 and with SIRT1 and SIRT2 siRNA
We have explored the role of sirtuin expression and activity in the proliferation and survival of synovial sarcoma and rhabdomyosarcoma cell lines
Summary
Seven sirtuins (SIRT1-7) have been identified in mammals, all of them sharing the NAD+ binding and catalytic domain, but targeting different substrates and distinct but not exclusive subcellular localizations. Sirtuins are associated with cancer, as they deacetylate cancer-associated transcription factors. This was first demonstrated for SIRT1 that deacetylates lysine 382 of the p53 tumor suppressor protein (K382-p53), a post-translational modification that favors p53 degradation.[4,5,6]. SIRT1 is overexpressed in different tumor types such as acute myeloid leukemia, colon and prostate cancers, but this correlation is not found for bladder carcinoma, glioblastoma nor ovarian cancer.[7] The oncogenic role of SIRT1 is controversial, as this sirtuin is involved in the maintenance of DNA integrity. Several studies support a role for SIRT2 as tumor suppressor protein. The alveolar rhabdomyosarcoma is characterized by the chromosomal translocation that fuses the PAX3 or PAX7 genes with the gene encoding the transcription factor FOXO1/FKHR
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