Function and regulation of SirT1 in cancer

描述（由申请人提供）：NAD依赖性组蛋白脱乙酰酶Sir 2在调节酵母中的基因沉默中起重要作用，并可延长几种模式生物的寿命。哺乳动物Sir 2的直系同源物SirT 1参与了生长停滞和细胞凋亡的关键因子的调节，包括p53，NF-？B和Forkhead。我们发现E2 F1在启动子水平调节SirT 1的表达。此外，SirT 1与E2 F1结合并抑制E2 F1的转录和凋亡功能，形成明显的负反馈环。SirT 1的敲低增加E2 F1转录和凋亡活性。依托泊苷引起的DNA损伤导致SirT 1的E2 F1依赖性诱导，并且SirT 1的敲低增加对依托泊苷的敏感性。这些结果揭示了E2 F1和SirT 1之间的相互调节，影响细胞对DNA损伤的敏感性。我们还发现，SirT 1的多个位点的磷酸化可以调节其脱乙酰酶活性。我们假设SirT 1的表达和活性受致癌和应激信号的调节，有助于肿瘤细胞的存活和治疗抗性。我们提出以下实验来研究SirT 1在肿瘤细胞中的作用，并评估靶向SirT 1在癌症治疗中的潜力。(1)研究E2 F1和SirT 1的相互调节。(2)确定SirT 1对肿瘤形成和治疗反应的影响。(3)研究磷酸化对SirT 1的调控。(4)研究SirT 1在核糖体应激反应中的作用。这些实验将有助于更好地理解SirT 1的作用，并可能发现新的癌症治疗靶点。

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.