Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

Abstract

Epithelial to mesenchymal transition (EMT) is a developmental program reactivated by tumor cells that leads to the switch from epithelial to mesenchymal phenotype. During EMT, cells are transcriptionally regulated to decrease E-cadherin expression while expressing mesenchymal markers such as vimentin, fibronectin, and N-cadherin. Growing body of evidences suggest that cells engaged in EMT undergo a metabolic reprograming process, redirecting glucose flux toward hexosamine biosynthesis pathway (HBP), which fuels aberrant glycosylation patterns that are extensively observed in cancer cells. HBP depends on nutrient availability to produce its end product UDP-GlcNAc, and for this reason is considered a metabolic sensor pathway. UDP-GlcNAc is the substrate used for the synthesis of major types of glycosylation, including O-GlcNAc and cell surface glycans. In general, the rate limiting enzyme of HBP, GFAT, is overexpressed in many cancer types that present EMT features as well as aberrant glycosylation. Moreover, altered levels of O-GlcNAcylation can modulate cell morphology and favor EMT. In this review, we summarize some of the current knowledge that correlates glucose metabolism, aberrant glycosylation and hyper O-GlcNAcylation supported by HBP that leads to EMT activation. Developmental Dynamics 247:481-491, 2018. © 2017 Wiley Periodicals, Inc.

Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells

“…Our results were in agreement with other studies, showing that HIF-1α is essential for the dynamic transition of breast cancer tumorigenic states (Kuo et al, 2016) and involved in the breast cancer aggressiveness and tumor resistance by epigenetic regulation of glycosylation-related genes Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 (Greville et al, 2016). In addition, several studies have shown that the morphological changes occurring during EMT are accompanied by a metabolic shift towards glucose metabolism reprograming and aberrant glycosylation (Li and Li, 2015;Lucena et al, 2016;Carvalho et al, 2018).…”

Drug resistance related to aberrant glycosylation in colorectal cancer

“…Reduced levels of O -GlcNAcylation diminished the colorectal CSC compartment in vivo by overexpression of the epigenetic regulation of MYB proto-oncogene like 1 (MYBL1), a transcriptional activator of E-cadherin [ 149 ] (Figure 4D ). The key role of O -GlcNAcylation of other EMT actors has also been well highlighted [ 150 , 151 ]. The comprehension of the mechanisms underlying the role of O -GlcNAcylation in cell apoptosis remains at its beginnings.…”

MicroRNA‑206 regulates the epithelial‑mesenchymal transition and inhibits the invasion and metastasis of prostate cancer cells by targeting Annexin A2

“…N-cadherin is a cell surface adhesion molecule and a major structural element in intercellular adhesion. Its principal function is to mediate cell adhesion and migration ( 32 ). The expression of N-cadherin is increased in epithelial malignant tumors and is associated with the EMT ( 33 ).…”