Abstract：
SIRT6, an evolutionarily conserved histone deacetylase, has been identified as a novel direct downstream target of Akt/FoxO3a and a tumor suppressor in colon cancer in our previous research. Nevertheless, the precise mechanisms through which SIRT6 hinders tumor development remain unclear. To ascertain whether SIRT6 directly impacts Survivin transcription, a ChIP assay was conducted using an anti-SIRT6 antibody to isolate DNA. YM155 was synthesized to explore Survivin\'s role in mitochondrial apoptosis, autophagy and tumor progression. Our investigation into the regulation of Survivin involved real-time fluorescence imaging in living cells, real-time PCR, immunohistochemistry, flow cytometry, and xenograft mouse assays. In this current study, we delved into the role of SIRT6 in colon cancer and established that activated SIRT6 triggers mitochondrial apoptosis by reducing Survivin expression. Subsequent examinations revealed that SIRT6 directly binds to the Survivin promoter, impeding its transcription. Notably, direct inhibition of Survivin significantly impeded colon cancer proliferation by inducing mitochondrial apoptosis and autophagy both in vitro and in vivo. More interestingly, Survivin inhibition reactivated the Akt/FoxO3a pathway and elevated SIRT6 levels, establishing a positive feedback loop. Our results identify Survivin as a novel downstream transcriptional target of SIRT6 that fosters tumor growth and holds promise as a prospective target for colon cancer therapy.
摘要：
SIRT6，一种进化保守的组蛋白脱乙酰酶，在我们先前的研究中，已被确定为Akt/FoxO3a的新的直接下游靶标和结肠癌的肿瘤抑制因子。然而，SIRT6阻碍肿瘤发展的确切机制尚不清楚.为了确定SIRT6是否直接影响Survivin转录，使用抗SIRT6抗体进行ChIP测定以分离DNA。合成YM155以探讨Survivin在线粒体凋亡中的作用，自噬与肿瘤进展。我们对Survivin调节的研究涉及活细胞中的实时荧光成像，实时PCR，免疫组织化学，流式细胞术,和异种移植小鼠试验。在目前的研究中,我们深入研究了SIRT6在结肠癌中的作用,并确定激活的SIRT6通过降低Survivin表达触发线粒体凋亡.随后的检查显示SIRT6直接与Survivin启动子结合，阻碍它的转录。值得注意的是,Survivin的直接抑制通过诱导线粒体凋亡和自噬在体外和体内显着阻碍结肠癌的增殖。更有趣的是，Survivin抑制重新激活Akt/FoxO3a通路和升高的SIRT6水平，建立正反馈循环。我们的结果将Survivin确定为SIRT6的新型下游转录靶标，可促进肿瘤生长，并有望成为结肠癌治疗的前瞻性靶标。
