title: Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling.
abstract: Cancer stem cells (CSCs) represent a small subpopulation of self-renewing oncogenic cells. As in many other stem cells, metabolic reprogramming has been implicated to be a key characteristic of CSCs. However, little is known about how the metabolic features of cancer cells are controlled to orchestrate their CSC-like properties. We recently demonstrated that hyaluronan (HA) overproduction allowed plastic cancer cells to revert to stem cell states. Here, we adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells. These integrated approaches disclosed an acceleration of metabolic flux in the hexosamine biosynthetic pathway (HBP). A metabolic shift toward glycolysis was also evident by quantitative targeted metabolomics, which was validated by the expression profiles of key glycolytic enzymes. Forced expression of glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), an HBP rate-limiting enzyme, resembled the results of HA overproduction with regard to HIF-1α accumulation and glycolytic program, whereas GFAT1 inhibition significantly decreased HIF-1α protein level in HA-overproducing cancer cells. Moreover, inhibition of the HBP-HIF-1 axis abrogated HA-driven glycolytic enhancement and reduced the CSC-like subpopulation. Taken together, our results provide compelling evidence that HA production regulates the metabolic and CSC-like properties of breast cancer cells via HBP-coupled HIF-1 signaling.
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and.
authors.forename: Theerawut
authors.initials: T
authors.lastname: Chanmee
authors.affiliation: the Division of Engineering (Biotechnology), Graduate School of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
authors.forename: Pawared
authors.initials: P
authors.lastname: Ontong
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Izumikawa
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and.
authors.forename: Miho
authors.initials: M
authors.lastname: Higashide
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Mochizuki
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and.
authors.forename: Chatchadawalai
authors.initials: C
authors.lastname: Chokchaitaweesuk
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and.|the Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Manatsanan
authors.initials: M
authors.lastname: Khansai
authors.affiliation: the Division of Clinical Research Promotion and Support Center for Research Promotion, Fujita Health University School, Toyoake 470-1192, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: the Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan, and.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kakizaki
authors.affiliation: the Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Prachya
authors.initials: P
authors.lastname: Kongtawelert
authors.affiliation: the Disease Glycomics Team, Systems Glycobiology Research Group, Global Research Cluster, RIKEN-Max Planck Joint Research Center, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.affiliation: From the Department of Molecular Biosciences, Faculty of Life Sciences, and itanon@cc.kyoto-su.ac.jp.|the Division of Engineering (Biotechnology), Graduate School of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Itano
mesh_terms: D000818:Animals; D005260:Female; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D006595:Hexosamines / Q000096:biosynthesis* / Q000235:genetics; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019884:Nitrogenous Group Transferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006595:Hexosamines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D006820:Hyaluronic Acid; D019884:Nitrogenous Group Transferases; C488523:Gfpt1 protein, mouse; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
keywords: cancer stem cells; cell metabolism; glycolysis; hexosamine biosynthetic pathway; hyaluronan; hypoxia-inducible factor (HIF)