Pinho Salomé S, Reis Celso A, Paredes Joana, Magalhães Ana Maria, Ferreira António Carlos, Figueiredo Joana, Xiaogang Wen, Carneiro Fátima, Gärtner Fátima, Seruca Raquel
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal.
Hum Mol Genet. 2009 Jul 15;18(14):2599-608. doi: 10.1093/hmg/ddp194. Epub 2009 Apr 29.
It has long been recognized that E-cadherin dysfunction is a major cause of epithelial cell invasion. However, very little is known about the post-transcriptional modifications of E-cadherin and its role in E-cadherin mediated tumor progression. N-acetylglucosaminyltransferase III (GnT-III) catalyzes the formation of a bisecting GlcNAc structure in N-glycans, and has been pointed as a metastasis suppressor. N-acetylglucosaminyltransferase V (GnT-V) catalyzes the addition of beta1,6 GlcNAc branching of N-glycans, and has been associated to increase metastasis. The regulatory mechanism between E-cadherin expression and the remodeling of its oligosaccharides structures by GnT-III and GnT-V were explored in this study. We have demonstrated that wild-type E-cadherin regulates MGAT3 gene transcription resulting in increased GnT-III expression. We also showed that GnT-III and GnT-V competitively modified E-cadherin N-glycans. The GnT-III knockdown cells revealed a membrane de-localization of E-cadherin leading to its cytoplasmic accumulation. Further, the GnT-III knockdown cells also caused modifications of E-cadherin N-glycans catalyzed by GnT-III and GnT-V. Altogether our results have clarified the existence of a bidirectional crosstalk between E-cadherin and GnT-III/GnT-V that was, for the first time, reproduced in an in vivo model. This study opens new insights into the post-transcriptional modifications of E-cadherin in its biological function, in a tumor context.
长期以来，人们一直认为E-钙黏蛋白功能障碍是上皮细胞侵袭的主要原因。然而，对于E-钙黏蛋白的转录后修饰及其在E-钙黏蛋白介导的肿瘤进展中的作用知之甚少。N-乙酰葡糖胺基转移酶III（GnT-III）催化在N-聚糖中形成平分型GlcNAc结构，并被认为是一种转移抑制因子。N-乙酰葡糖胺基转移酶V（GnT-V）催化N-聚糖的β1,6 GlcNAc分支的添加，并与转移增加有关。本研究探讨了E-钙黏蛋白表达与GnT-III和GnT-V对其寡糖结构重塑之间的调控机制。我们已经证明野生型E-钙黏蛋白调节MGAT3基因转录，导致GnT-III表达增加。我们还表明GnT-III和GnT-V竞争性修饰E-钙黏蛋白的N-聚糖。GnT-III敲低的细胞显示E-钙黏蛋白的膜去定位，导致其在细胞质中积累。此外，GnT-III敲低的细胞还导致了由GnT-III和GnT-V催化的E-钙黏蛋白N-聚糖的修饰。总之，我们的结果阐明了E-钙黏蛋白与GnT-III/GnT-V之间双向串扰的存在，这首次在体内模型中得到重现。这项研究为肿瘤背景下E-钙黏蛋白在其生物学功能中的转录后修饰提供了新的见解。
