NF-κB upregulates glutamine-fructose-6-phosphate transaminase 2 to promote migration in non-small cell lung cancer

Epithelial-to-mesenchymal transition (EMT) results in changes that promote de-differentiation, migration, and invasion in non-small cell lung cancer (NSCLC). While it is recognized that EMT promotes altered energy utilization, identification of metabolic pathways that link EMT with cancer progressio...

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Published in:	Cell communication and signaling Vol. 17; no. 1; p. 24
Main Authors:	Szymura, Szymon J, Zaemes, Jacob P, Allison, David F, Clift, Sheena H, D'Innocenzi, Jaclyn M, Gray, Lisa G, McKenna, Brian D, Morris, Benjamin B, Bekiranov, Stefan, LeGallo, Robin D, Jones, David R, Mayo, Marty W
Format:	Journal Article
Language:	English
Published:	England BioMed Central 18-03-2019 BMC
Subjects:	A549 Cells Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Cell migration Cell Movement Epithelial-mesenchymal transition Gene Expression Regulation, Neoplastic Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - metabolism Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) HEK293 Cells Humans Lung Neoplasms - genetics Lung Neoplasms - pathology NF-kappa B - metabolism Non-small cell lung cancer (NSCLC) Nuclear factor kappa B (NF-κB) Signal Transduction Sirtuin-6 (SIRT6) Sirtuins - metabolism Transcriptional Activation Nuclear factor kappa B (NF-κB) Epithelial-mesenchymal transition Sirtuin-6 (SIRT6) Cell migration Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) Non-small cell lung cancer (NSCLC)
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Summary:	Epithelial-to-mesenchymal transition (EMT) results in changes that promote de-differentiation, migration, and invasion in non-small cell lung cancer (NSCLC). While it is recognized that EMT promotes altered energy utilization, identification of metabolic pathways that link EMT with cancer progression is needed. Work presented here indicates that mesenchymal NSCLC upregulates glutamine-fructose-6-phosphate transaminase 2 (GFPT2). GFPT2 is the rate-limiting enzyme in the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the obligate activator of O-linked N-acetylglucosamine transferase (OGT). Analysis of our transcriptomic data indicates that GFPT2 is one of the most significantly upregulated metabolic genes in mesenchymal NSCLC. Ectopic GFPT2 expression, as well as gene silencing strategies were used to determine the importance of this metabolic enzyme in regulating EMT-driven processes of cell motility and invasion. Our work demonstrates that GFPT2 is transcriptionally upregulated by NF-κB and repressed by the NAD -dependent deacetylase SIRT6. Depletion of GFPT2 expression in NSCLC highlights its importance in regulating cell migration and invasion during EMT. Consistent with GFPT2 promoting cancer progression, we find that elevated GFPT2 expression correlates with poor clinical outcome in NSCLC. Modulation of GFPT2 activity offers a potentially important therapeutic target to combat NSCLC disease progression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1478-811X 1478-811X
DOI:	10.1186/s12964-019-0335-5