title: Epithelial Mesenchymal Transition Induces Aberrant Glycosylation through Hexosamine Biosynthetic Pathway Activation.
abstract: Deregulated cellular metabolism is a hallmark of tumors. Cancer cells increase glucose and glutamine flux to provide energy needs and macromolecular synthesis demands. Several studies have been focused on the importance of glycolysis and pentose phosphate pathway. However, a neglected but very important branch of glucose metabolism is the hexosamine biosynthesis pathway (HBP). The HBP is a branch of the glucose metabolic pathway that consumes ∼2-5% of the total glucose, generating UDP-GlcNAc as the end product. UDP-GlcNAc is the donor substrate used in multiple glycosylation reactions. Thus, HBP links the altered metabolism with aberrant glycosylation providing a mechanism for cancer cells to sense and respond to microenvironment changes. Here, we investigate the changes of glucose metabolism during epithelial mesenchymal transition (EMT) and the role of O-GlcNAcylation in this process. We show that A549 cells increase glucose uptake during EMT, but instead of increasing the glycolysis and pentose phosphate pathway, the glucose is shunted through the HBP. The activation of HBP induces an aberrant cell surface glycosylation and O-GlcNAcylation. The cell surface glycans display an increase of sialylation α2-6, poly-LacNAc, and fucosylation, all known epitopes found in different tumor models. In addition, modulation of O-GlcNAc levels was demonstrated to be important during the EMT process. Taken together, our results indicate that EMT is an applicable model to study metabolic and glycophenotype changes during carcinogenesis, suggesting that cell glycosylation senses metabolic changes and modulates cell plasticity.
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho.
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Lucena
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho.
authors.forename: Patricia
authors.initials: P
authors.lastname: Carvalho-Cruz
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho.
authors.forename: Joana L
authors.initials: JL
authors.lastname: Donadio
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho.
authors.forename: Isadora A
authors.initials: IA
authors.lastname: Oliveira
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho.
authors.forename: Rafaela M
authors.initials: RM
authors.lastname: de Queiroz
authors.affiliation: Faculdade de Farmácia, and.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Marinho-Carvalho
authors.affiliation: Faculdade de Farmácia, and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Sola-Penna
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil and.
authors.forename: Iron F
authors.initials: IF
authors.lastname: de Paula
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil and.
authors.forename: Katia C
authors.initials: KC
authors.lastname: Gondim
authors.affiliation: the Department of Biochemistry, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Mark E
authors.initials: ME
authors.lastname: McComb
authors.affiliation: the Department of Biochemistry, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.affiliation: the Department of Biochemistry, Cardiovascular Proteomics Center, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Whelan
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho.
authors.forename: Adriane R
authors.initials: AR
authors.lastname: Todeschini
authors.affiliation: From the Instituto de Biofísica Carlos Chagas Filho, diaswb@biof.ufrj.br.
authors.forename: Wagner B
authors.initials: WB
authors.lastname: Dias
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D058750:Epithelial-Mesenchymal Transition; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006031:Glycosylation; D006595:Hexosamines / Q000096:biosynthesis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D019289:Pyruvic Acid / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D006595:Hexosamines; D016212:Transforming Growth Factor beta; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D006003:Glycogen; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; D005947:Glucose
keywords: GFAT; HBP; O-GlcNAcylation; O-linked N-acetylglucosamine (O-GlcNAc); O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT); cancer; epithelial-mesenchymal transition (EMT); glucose metabolism; glycosylation; hexosamine biosynthetic pathway