title: Protein Sialylation Regulates a Gene Expression Signature that Promotes Breast Cancer Cell Pathogenicity.
abstract: Many mechanisms have been proposed for how heightened aerobic glycolytic metabolism fuels cancer pathogenicity, but there are still many unexplored pathways. Here, we have performed metabolomic profiling to map glucose incorporation into metabolic pathways upon transformation of mammary epithelial cells by 11 commonly mutated human oncogenes. We show that transformation of mammary epithelial cells by oncogenic stimuli commonly shunts glucose-derived carbons into synthesis of sialic acid, a hexosamine pathway metabolite that is converted to CMP-sialic acid by cytidine monophosphate N-acetylneuraminic acid synthase (CMAS) as a precursor to glycoprotein and glycolipid sialylation. We show that CMAS knockdown leads to elevations in intracellular sialic acid levels, a depletion of cellular sialylation, and alterations in the expression of many cancer-relevant genes to impair breast cancer pathogenicity. Our study reveals the heretofore unrecognized role of sialic acid metabolism and protein sialylation in regulating the expression of genes that maintain breast cancer pathogenicity.
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Kohnz
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Roberts
authors.affiliation: Department of Electrical Engineering and Computer Science, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: David
authors.initials: D
authors.lastname: DeTomaso
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Lara
authors.initials: L
authors.lastname: Bideyan
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Yan
authors.affiliation: Division of Hematology/Oncology, Department of Cell and Tissue Biology, University of California, San Francisco , 513 Parnassus Avenue HSW616, San Francisco, California 94143, United States.|University of California , San Francisco Helen Diller Family Comprehensive Cancer Center, Box 0128, San Francisco, California 94143, United States.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: Division of Hematology/Oncology, Department of Cell and Tissue Biology, University of California, San Francisco , 513 Parnassus Avenue HSW616, San Francisco, California 94143, United States.|University of California , San Francisco Helen Diller Family Comprehensive Cancer Center, Box 0128, San Francisco, California 94143, United States.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: Department of Electrical Engineering and Computer Science, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.affiliation: Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D055432:Metabolomics; D016513:Mice, SCID; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D000216:N-Acylneuraminate Cytidylyltransferase / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D009363:Neoplasm Proteins; D000216:N-Acylneuraminate Cytidylyltransferase; D019158:N-Acetylneuraminic Acid