Department of Biology, School of Life Sciences, Shanxi University, Taiyuan, Shanxi, PR China.
Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong SAR, PR China.
J Cell Physiol. 2019 Nov;234(11):20694-20703. doi: 10.1002/jcp.28674. Epub 2019 Apr 15.
We have recently published that type 2 diabetes can induce cell centrosome amplification due to the action of high glucose, palmitic acid, and insulin, and ROCK1 and 14-3-3σ are signal mediators. In this study, we further investigated the molecular mechanisms of the centrosome amplification in colon cancer HCT116 cells. Treatment of the cells with high glucose, palmitic acid, and insulin increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) as well as the spindle and kinetochore associated protein 1 (SKA1), knockdown of each of which resulted in the inhibition of the treatment-triggered centrosome amplification. Knockdown of PPARγ inhibited the treatment-evoked increase in the SKA1 level, whereas knockdown of SKA1 did not modify the treatment-increased PPARγ level. We found a predicted binding site for PPARγ in the promoter region of the SKA1 gene from the JASPAR database. Experimental results showed that the treatment increased the messenger RNA level of SKA1, which could be inhibited by PPARγ chemical inhibitor or small interfering RNA. Moreover, we were able to show that PPARγ could bind to the binding site in the SKA1 gene promoter, which was increased by the experimental treatment. In conclusion, it is suggested that the pathophysiological factors in type 2 diabetes, high glucose, palmitic acid, and insulin, induce the cell centrosome amplification through the PPARγ-SKA1 pathway, in which PPARγ increases the expression of SKA1 via directly enhancing the SKA1 gene transcription.
我们最近发表的研究表明，2 型糖尿病可以通过高葡萄糖、棕榈酸和胰岛素的作用诱导细胞中心体扩增，ROCK1 和 14-3-3σ 是信号介导物。在这项研究中，我们进一步研究了结肠癌 HCT116 细胞中心体扩增的分子机制。用高葡萄糖、棕榈酸和胰岛素处理细胞会增加过氧化物酶体增殖物激活受体 γ（PPARγ）以及纺锤体和动粒相关蛋白 1（SKA1）的表达，敲低其中任何一种都会抑制治疗引发的中心体扩增。PPARγ 的敲低抑制了治疗引起的 SKA1 水平的增加，而 SKA1 的敲低并没有改变治疗增加的 PPARγ 水平。我们从 JASPAR 数据库中发现了 SKA1 基因启动子区域中预测的 PPARγ 结合位点。实验结果表明，治疗可增加 SKA1 的信使 RNA 水平，这可被 PPARγ 化学抑制剂或小干扰 RNA 抑制。此外，我们能够表明，PPARγ 可以结合到 SKA1 基因启动子中的结合位点，该结合位点在实验处理后增加。总之，建议 2 型糖尿病的病理生理因素，高葡萄糖、棕榈酸和胰岛素通过 PPARγ-SKA1 途径诱导细胞中心体扩增，其中 PPARγ 通过直接增强 SKA1 基因转录来增加 SKA1 的表达。
