Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China; School of Biomedical Sciences, Hunan University, Changsha, China.
Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China; Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
Mitochondrion. 2024 Sep;78:101932. doi: 10.1016/j.mito.2024.101932. Epub 2024 Jul 8.
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.
SIRT6 是一种进化上保守的组蛋白去乙酰化酶，在我们之前的研究中被鉴定为 Akt/FoxO3a 的一个新的直接下游靶点，也是结肠癌的一种肿瘤抑制因子。然而，SIRT6 抑制肿瘤发生的确切机制尚不清楚。为了确定 SIRT6 是否直接影响 Survivin 的转录，我们使用抗 SIRT6 抗体进行了 ChIP 分析以分离 DNA。合成了 YM155 来研究 Survivin 在线粒体凋亡、自噬和肿瘤进展中的作用。我们通过实时荧光成像、实时 PCR、免疫组织化学、流式细胞术和异种移植小鼠实验来研究 Survivin 的调节。在本研究中，我们深入研究了 SIRT6 在结肠癌中的作用，发现激活的 SIRT6 通过降低 Survivin 的表达来触发线粒体凋亡。进一步的研究表明，SIRT6 直接与 Survivin 启动子结合，抑制其转录。值得注意的是，直接抑制 Survivin 通过诱导线粒体凋亡和自噬，在体外和体内均显著抑制结肠癌的增殖。更有趣的是， Survivin 抑制作用通过激活 Akt/FoxO3a 通路并提高 SIRT6 水平，建立了一个正反馈回路。我们的研究结果确定 Survivin 是 SIRT6 的一个新的下游转录靶标，促进肿瘤生长，并有望成为结肠癌治疗的一个潜在靶点。
