Function and regulation of SirT1 in cancer

描述(申请人提供)：依赖NAD的组蛋白去乙酰基酶Sir2在调节酵母中的基因沉默方面发挥重要作用，并可以延长几种模式生物的寿命。哺乳动物Sir2基因SirT1参与调控细胞生长停滞和细胞凋亡的关键因子，包括P53、NF-β和Forkhead。我们发现，E2F1在启动子水平上调节SirT1的表达。此外，SirT1与E2F1结合并抑制E2F1的转录和凋亡功能，形成一个明显的负反馈环。SirT1基因敲除可增加E2F1转录和细胞凋亡活性。依托泊苷对DNA的损伤导致依赖于E2F1的SirT1的诱导，而SirT1的敲除增加了对依托泊苷的敏感性。这些结果揭示了E2F1和SirT1之间的相互调节，影响了细胞对DNA损伤的敏感性。我们还发现，SirT1在多个位点上的磷酸化可能调节其脱乙酰酶的活性。我们假设SirT1的表达和活性受致癌信号和应激信号的调节，有助于肿瘤细胞的存活和治疗耐药。我们提出了以下实验来研究SirT1在肿瘤细胞中的作用，并评估靶向SirT1在癌症治疗中的潜力。(1)研究E2F1和SirT1的相互调控。(2)检测SirT1对肿瘤形成和治疗反应的影响。(3)研究SirT1的磷酸化调控。(4)探讨SirT1在核糖体应激反应中的作用。这些实验应该有助于更好地理解SirT1的作用，并可能确定癌症的新治疗靶点。

DESCRIPTION (provided by applicant): The NAD-dependent histone deacetylase Sir2 plays important roles in regulating gene silencing in yeast and can extend the life span of several model organisms. The mammalian Sir2 ortholog SirT1 has been implicated in the regulation of key factors involved in growth arrest and apoptosis, including p53, NF-?b and Forkhead. We have found that E2F1 regulates SirT1 expression at the promoter level. Furthermore, SirT1 binds to E2F1 and inhibits E2F1 transcriptional and apoptosis functions, forming an apparent negative feedback loop. Knockdown of SirT1 increases E2F1 transcriptional and apoptosis activities. DNA damage by etoposide causes E2F1-dependent induction of SirT1, and knockdown of SirT1 increases sensitivity to etoposide. These results reveal a mutual regulation between E2F1 and SirT1 that affects cellular sensitivity to DNA damage. We also found that phosphorylation of SirT1 on multiple sites may regulate its deacetylase activity. We hypothesize that SirT1 expression and activity are regulated by oncogenic and Stress signals, contributing to tumor cell survival and treatment resistance. We propose the following experiments to investigate the role of SirT1 in tumor cells, and to evaluate the potential of targeting SirT1 in cancer therapy. (1) Investigate the mutual regulation of E2F1 and SirT1. (2) Determine the effects of SirT1 on tumor formation and treatment response. (3) Investigate the regulation of SirT1 by phosphorylation. (4) Investigate the role of SirT1 in ribosomal stress response. These experiments should lead to a better understanding of the role of SirT1 and may identify novel therapeutic targets for cancer.