Mathow Daniel, Chessa Federica, Rabionet Mariona, Kaden Sylvia, Jennemann Richard, Sandhoff Roger, Gröne Hermann-Josef, Feuerborn Alexander
Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Cellular and Molecular Pathology, Lipid Pathobiochemistry Group German Cancer Research Center (DKFZ), Heidelberg, Germany.
EMBO Rep. 2015 Mar;16(3):321-31. doi: 10.15252/embr.201439333. Epub 2015 Feb 2.
This study proposes that the transcription factor Zeb1 modulates epithelial cell adhesion by diverting glycosphingolipid metabolism. Zeb1 promotes expression of a-series glycosphingolipids via regulating expression of GM3 synthase (St3gal5), which mechanistically involves Zeb1 binding to the St3gal5 promoter as well as suppressing microRNA-mediated repression of St3gal5. Functionally, the repression of St3gal5 suffices to elevate intercellular adhesion and expression of distinct junction-associated proteins, reminiscent of knockdown of Zeb1. Conversely, overexpressing St3gal5 sensitizes cells towards TGF-β1-induced disruption of cell-cell interaction and partially antagonizes elevation of intercellular adhesion imposed by Zeb1 knockdown. These results highlight a direct connection of glycosphingolipid metabolism and epithelial cell adhesion via Zeb1.
本研究提出,转录因子Zeb1通过改变糖鞘脂代谢来调节上皮细胞黏附。Zeb1通过调节GM3合酶(St3gal5)的表达来促进a系列糖鞘脂的表达,其机制涉及Zeb1与St3gal5启动子的结合以及抑制微小RNA介导的对St3gal5的抑制作用。在功能上,对St3gal5的抑制足以提高细胞间黏附以及不同的连接相关蛋白的表达,这与敲低Zeb1的情况相似。相反,过表达St3gal5会使细胞对TGF-β1诱导的细胞间相互作用破坏敏感,并部分拮抗Zeb1敲低所导致的细胞间黏附增加。这些结果突出了通过Zeb1实现的糖鞘脂代谢与上皮细胞黏附之间的直接联系。