RRC ID 47460
Author Chanmee T, Ontong P, Izumikawa T, Higashide M, Mochizuki N, Chokchaitaweesuk C, Khansai M, Nakajima K, Kakizaki I, Kongtawelert P, Taniguchi N, Itano N.
Title Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling.
Journal J Biol Chem
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.
Volume 291(46)
Pages 24105-24120
Published 2016-11-11
DOI 10.1074/jbc.M116.751263
PII S0021-9258(20)34680-9
PMID 27758869
PMC PMC5104936
MeSH Animals Female Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) Hexosamines / biosynthesis* Hexosamines / genetics Hyaluronic Acid / biosynthesis* Hyaluronic Acid / genetics Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Mammary Neoplasms, Experimental / genetics Mammary Neoplasms, Experimental / metabolism* Mammary Neoplasms, Experimental / pathology Mice Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Neoplastic Stem Cells / metabolism* Neoplastic Stem Cells / pathology Nitrogenous Group Transferases / genetics Nitrogenous Group Transferases / metabolism Signal Transduction*
IF 4.238
Times Cited 29
DNA material AxCANCre (RDB01748)