Journal
ONCOTARGET
Volume 7, Issue 40, Pages 65231-65246Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11245
Keywords
E-cadherin; O-mannosylation; N-glycosylation; gastric cancer
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Funding
- FCT, the Portuguese Foundation for Science and Technology
- FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal
- Portuguese funds through FCT [POCI-01-0145-FEDER-007274]
- Deutsche Forschungsgemeinschaft [Sonderforschungsbereich 1036]
- [PTDC/DTP-PIC/0560/2014]
- [PTDC/BBB-EBI/0567/20141]
- [SERH/BD/77386/2011]
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Dysregulation of tumor suppressor protein E-cadherin is an early molecular event in cancer. O-mannosylation profile of E-cadherin is a newly-described post-ranslational modification crucial for its adhesive functions in homeostasis. However, the role of O-mannosyl glycans in E-cadherin-mediated cell adhesion in cancer and their interplay with N-glycans remains largely unknown. We herein demonstrated that human gastric carcinomas exhibiting a non-functional E-cadherin display a reduced expression of O-mannosyl glycans concomitantly with increased modification with branched complex N-glycans. Accordingly, overexpression of MGAT5-mediated branched N-glycans both in gastric cancer cells and transgenic mice models led to a significant decrease of O-mannosyl glycans attached to E-cadherin that was associated with impairment of its tumour suppressive functions. Importantly, overexpression of protein O-mannosyltransferase 2 (POMT2) induced a reduced expression of branched N-glycans which led to a protective effect of E-cadherin biological functions. Overall, our results reveal a newly identified mechanism of (dys) regulation of E-cadherin that occur through the interplay between O-mannosylation and N-glycosylation pathway.
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