Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation (original) (raw)
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Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options
International Journal of Molecular Sciences
Recent advances in glioblastoma (GB) research have shed light on the molecular characteristics, the defected intracellular signaling pathways, and the genetic and epigenetic alterations involved in their pathogenesis. Despite constant efforts, GB remains an aggressive malignant tumor with limited therapeutic approaches, poor prognosis, and a low survival rate. Emerging evidence points towards the crucial impact of epigenetic post-translational modifications in cancer development with emphasis on the regulatory role of histone deacetylation in several key cellular processes, including metabolic pathways, regulation of stress response, senescence, proliferation, DNA repair, and apoptosis. The silent information regulator proteins (Sirtuins) are deacetylases of histone and non-histone proteins that have been recently implicated in the initiation as well as in the progression of GB. Herein, we provide a critical overview of the emerging functional role and mechanism of action of the sev...
Febs Letters, 2009
To examine the function of SIRT1 in neuronal differentiation, we employed all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. Nicotinamide inhibited neurite outgrowth and tyrosine hydroxylase (TH) expression. Inhibition of PARP or histone deacetylase did not inhibit TH expression, showing the effect to be SIRT1 specific. Expression of FOXO3a and its target proteins were increased during the differentiation and reduced by nicotinamide. FOXO3a deacetylation was increased by ATRA and blocked by nicotinamide. SIRT1 and FOXO3a siRNA inhibited ATRA-induced up-regulation of TH and differentiation. Taken together, these results indicate that SIRT1 is involved in ATRA-induced differentiation of neuroblastoma cells via FOXO3a.
Sirtuin 1 regulation of developmental genes during differentiation of stem cells
Proceedings of The National Academy of Sciences, 2010
The longevity-promoting NAD + -dependent class III histone deacetylase Sirtuin 1 (SIRT1) is involved in stem cell function by controlling cell fate decision and/or by regulating the p53-dependent expression of NANOG. We show that SIRT1 is down-regulated precisely during human embryonic stem cell differentiation at both mRNA and protein levels and that the decrease in Sirt1 mRNA is mediated by a molecular pathway that involves the RNA-binding protein HuR and the arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1). SIRT1 down-regulation leads to reactivation of key developmental genes such as the neuroretinal morphogenesis effectors DLL4, TBX3, and PAX6, which are epigenetically repressed by this histone deacetylase in pluripotent human embryonic stem cells. Our results indicate that SIRT1 is regulated during stem cell differentiation in the context of a yet-unknown epigenetic pathway that controls specific developmental genes in embryonic stem cells.
Neuro-oncology, 2015
Cancer stemness, observed in several types of glioma stem cells (GSCs), has been demonstrated to be an important barrier for efficient cancer therapy. We have previously reported that cancerous neural stem cells (F3.Ras.CNSCs), derived from immortalized human neural stem cells by a single oncogenic stimulation, form glial tumors in vivo. We searched for a commonly expressed stress modulator in both F3.Ras.CNSCs and GSCs and identified silent mating type information regulation 2, homolog (SIRT1) as a key factor in maintaining cancer stemness. We demonstrate that the expression of SIRT1, expressed in "cancer cells with neural stemness," is critical not only for the maintenance of stem cells, but also for oncogenic transformation. Interestingly, SIRT1 is essential for the survival and tumorigenicity of F3.Ras.CNSCs and GSCs but not for the U87 glioma cell line. These results indicate that expression of SIRT1 in cancer cells with neural stemness plays an important role in supp...
Biochemical Pharmacology, 2019
Cell differentiation is a fundamental biological event in which a precursor stem cell is turning into a specialized somatic cell. It is thus crucial for the development, tissue turnover and regeneration in mammals. Among the numerous changes taking place in a cell during a differentiation programme, the biology of mitochondria, the central organelle mainly responsible for energy homeostasis and stress adaptation, is deeply modified. These modifications are now well recognized as taking an active part to the completion of the differentiation programme. Indeed, mitochondrial biogenesis and metabolic shift are observed during cell differentiation, adapting many syntheses, calcium homeostasis, ATP and reactive oxygen species production, to the needs. These mitochondrial functions are substantially regulated by the post-translational modifications of the mitochondrial proteins among which lysine acetylation is essential. This mitoacetylome is then globally controlled by the balance between spontaneous/enzymatically-catalysed protein acetylation and the NAD +-dependent deacetylation mediated by Sirtuin 3. This enzyme is now considered as a major regulator of the function of the organelle. Regarding the requirement of these mitochondrial adaptations, the subsequent growing interest for this enzyme recently extended to the investigation of the mechanisms driving cell differentiation. This review summarizes the currently available information about the significance of SIRT3 in cell differentiation in physio-pathological contexts. We also suggest a control of the differentiation-activated autophagy by SIRT3, a hypothesis supported by recent findings establishing a causal link between SIRT3 and autophagy. Eventually, an update on the present pharmacological modulators of SIRT3 in a context of cell differentiation is discussed.
Periodicum Biologorum
Sirtuins (SIRT) are group of enzymes that require nicotinamide adenine dinucleotide (NAD+) to catalyze their reactions. These chemical compounds have mono (ADP-ribosyl) transferase or deacetylases activities, and they can be found in nearly all species. The mammalian sirtuin family is described by seven proteins, namely. Every group of sirtuins can be found in the different regions of the cells; SIRT1 is predominantly nuclear, SIRT2 is located mainly in the cytoplasm (but it can shuttle between the nucleus and the cytoplasm), SIRT3, SIRT4, and SIRT5 are mitochondrial proteins, (SIRT3 can move from the nucleus to mitochondria during cellular stress), SIRT6 and SIRT7 are nuclear sirtuins. Sirtuins have a lot of functions in different physiological processes such as gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neu-roprotection, and healthy aging. Because of so many roles in physiological processes there is a huge interest not j...
miRNA regulation of Sirtuin-1 expression in human astrocytoma
Oncology Letters, 2016
Sirtuins are a family of 7 histone deacetylases largely involved in the regulation of cell proliferation, survival and death. The role of sirtuins in tumorigenesis and cancer progression has been previously studied in certain cancer types. Few studies have investigated sirtuin expression in gliomas, with controversial results. The aim of the present study was to investigate the expression of sirtuin-1 (Sirt-1) in diffuse astrocytoma [low grade astrocytoma (LGA)], anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) and in primary glioma cell lines: PLGAC (primary LGA cells); PAAC (primary AA cells); and PGBMC (primary GBM cells). Tumor samples were obtained from patients who underwent craniotomy for microsurgical tumor resection at the Neurosurgery Unit of the University of Messina between 2011 and 2014. Sirt-1 expression was qualitatively analyzed in 30 human glial tumor samples and 5 non-neoplastic brain tissue (NBT) specimens using immunohistochemistry and western blotting techniques. Sirt-1 expression was quantitatively analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, Sirt-1 expression in primary cell lines was investigated by immunoblotting and RT-qPCR. Sirt-1 expression was downregulated in gliomas compared to NBTs. Sirt-1 levels also varied among different tumor grades, with more evident downregulation in high-grade (P<0.001) than low-grade tumors (P<0.01). These data were confirmed in cell lines, with the exception of upregulation of protein level in the highest malignancy grade cell lines. The present results suggest a role for miRNA-34a, miRNA-132 and miRNA-217 in the epigenetic control of Sirt-1 during gliomagenesis and progression, and demonstrate the different implications of Sirt-1 in human tissues and cell lines. Furthermore, the present results reveal that Sirt-1 may be an intrinsic regulator of tumor progression and the regulation of Sirt-1 involves complex molecular pathways. However, the biological functions of Sirt-1 in gliomagenesis require additional investigation.
Sirtuin 7 in cell proliferation, stress and disease: Rise of the Seventh Sirtuin!
Cellular Signalling, 2014
Sirtuin 7 is a member of the sirtuin family of proteins. Sirtuins were originally discovered in yeast for its role in prolonging replicative lifespan. Until recently SIRT7 happened to be the least studied sirtuin of the seven mammalian sirtuins. However, a number of recent breakthrough reports have provided significant clarity to SIRT7 biology. SIRT7 is now seen as a vital regulator of rRNA and protein synthesis for maintenance of normal cellular homeostasis. Proteins like p53, H3K18, PAF53, NPM1 and GABP-β1 are the known substrates for the deacetylase activity of SIRT7, thereby making it a key mediator of many cellular activities. Studies using in vitro based assays and also knockout mice have revealed a role of SIRT7 in certain disease pathologies as well. High expression of SIRT7 has been reported in few cancer types and is steadily propelling SIRT7 towards an oncogene status. The role of SIRT7 as a pro-survival adaptor molecule in conditions of cellular stress has recently emerged in view of the fact that SIRT7 can regulate molecules like HIF and IRE1α. Additionally, SIRT7 plays a key role in maintenance of the epigenome as it caused the deacetylation of histone (H3K18) and global proteomics studies have shown its interaction with many chromatin remodelling complexes such as B-WICH and other proteins. Lately, the role of SIRT7 in hepatic lipid metabolism has been debated. This review attempts to summarize these recent findings and present the role of SIRT7 as an important cellular regulator.