Expression patterns and potential roles of SIRT1 in human medulloblastoma cells in vivo and in vitro
Liaoning Laboratory of Cancer Genetics and Epigenetics, Department of Cell Biology, Dalian Medical University, Dalian Department of Pathology, Sheng-Jing Hospital, China Medical University, Shenyang, China. Neuropathology
(Impact Factor: 1.65).
04/2012; 33(1). DOI: 10.1111/j.1440-1789.2012.01318.x
Medulloblastoma is a primitive neuroectodermal tumor, which originates in the cerebellum, presumably due to the alterations of some neurogenetic elements. Sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), regulates differentiation of neuronal stem cells but its status in medulloblastomas remains largely unknown. The current study aimed to address this issue by checking SIRT1 expression in noncancerous cerebellar tissues, medulloblastoma tissues and established cell lines. The roles of SIRT1 in proliferation and survival of UW228-3 medulloblastoma cells were analyzed by SIRT1 small interfering RNA (siRNA) transfection and SIRT1 inhibitor nicotinamide treatment. The results revealed that the frequency of SIRT1 expression in medulloblastoma tissues was 64.17% (77/120), while only one out of seven tumor-surrounding noncancerous cerebellar tissues showed restricted SIRT1 expression in the cells within the granule layer. Of the three morphological subtypes, the rates of SIRT1 detection in the large cell/anaplastic cell (79.07%; 34/43) and the classic medulloblastomas (60.29%; 41/68) are higher than that (22.22%; 2/9) in nodular/desmoplastic medulloblastomas (P < 0.01 and P < 0.05, respectively). Heterogeneous SIRT1 expression was commonly observed in classic medulloblastoma. Inhibition of SIRT1 expression by siRNA arrested 64.96% of UW228-3 medulloblastoma cells in the gap 1 (G1) phase and induced 14.53% of cells to apoptosis at the 48-h time point. Similarly, inhibition of SIRT1 enzymatic activity with nicotinamide brought about G1 arrest and apoptosis in a dose-related fashion. Our data thus indicate: (i) that SIRT1 may act as a G1-phase promoter and a survival factor in medulloblastoma cells; and (ii) that SIRT1 expression is correlated with the formation and prognosis of human medulloblastomas. In this context, SIRT1 would be a potential therapeutic target of medulloblastomas.
Available from: PubMed Central
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ABSTRACT: Sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein lysine modifying enzymes with deacetylase, adenosine diphosphateribosyltransferase and other deacylase activities. Mammals have seven sirtuins, namely SIRT1-7. They are key regulators for a wide variety of cellular and physiological processes such as cell proliferation, differentiation, DNA damage and stress response, genome stability, cell survival, metabolism, energy homeostasis, organ development, aging, and cancer. Here we present an extensive literature review of the roles of mammalian sirtuins, particularly SIRT1 as that is the most studied sirtuin, in human epithelial, neuronal, hematopoietic, and mesenchymal malignancies, covering breast, prostate, lung, thyroid, liver, colon, gastric, pancreatic, ovarian, and cervical cancers, tumors of the central nervous system, leukemia and lymphoma, and soft tissue sarcomas. Collective evidence suggests sirtuins are involved in both promoting and suppressing tumorigenesis depending on cellular and molecular contexts. We discuss the potential use of sirtuin modulators, especially sirtuin inhibitors, in cancer treatment.
Available from: John R P Knight
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ABSTRACT: The NAD(+)-dependent deacetylase SIRT1 is involved in diverse cellular processes, and has also been linked with multiple disease states. Among these, SIRT1 expression negatively correlates with cancer survival in both laboratory and clinical studies. Active regulator of SIRT1 (AROS) was the first reported post-transcriptional regulator of SIRT1 activity, enhancing SIRT1-mediated deacetylation and downregulation of the SIRT1 target p53. However, little is known regarding the role of AROS in regulation of SIRT1 during disease. Here, we report the cellular and molecular effects of RNAi-mediated AROS suppression, comparing this with the role of SIRT1 in a panel of human cell lines of both cancerous and non-cancerous origins. Unexpectedly, AROS is found to vary in its modulation of p53 acetylation according to cell context. AROS suppresses p53 acetylation only following the application of cell damaging stress, whereas SIRT1 suppresses p53 under all conditions analysed. This supplements the original characterization of AROS but indicates that SIRT1 activity can persist following suppression of AROS. We also demonstrate that knockdown of AROS induces apoptosis in three cancer cell lines, independent of p53 activation. Importantly, AROS is not required for the viability of three non-cancer cell lines indicating a putative role for AROS in specifically promoting cancer cell survival.
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ABSTRACT: Glioma accounts for most of primary malignant brain tumors and usually results in poor survival. However, the key signaling networks regulating glioma cell proliferation remain poorly defined. The forkhead box M1 (FoxM1) is a key transcription factor regulating multiple aspects of cell biology. Prior studies have shown that FoxM1 is overexpressed in glioma and plays a critical role in cancer development and progression.
Western blot and Real-time PCR assays were used to determine the regulation roles of FoxM1 on Sirt1 (Sirtuin1) expression. Small interfering RNAs (siRNAs) were used to silence the expression of FoxM1. Luciferase assays were used to measure binding of FoxM1 to the promoter region of Sirt1. Direct binding of FoxM1 to promoter of Sirt1 was assessed by chromatin immunoprecipitation (CHIP) assays.
We found that FoxM1 positively regulated mRNA expression of Sirt1. FoxM1 overexpression promoted while its knockdown inhibited Sirt1 expression. Besides, we identified a minimal FoxM1 binding site on the promoter region of Sirt1.
Our results for the first time add a new FoxM1-Sirt1 connection that mediates cell proliferation in glioma.
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