Expression patterns and potential roles of SIRT1 in human medulloblastoma cells in vivo and in vitro.

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.