Hyaluronan Production Regulates Metabolic and Cancer Stem-like Properties of Breast Cancer Cells via Hexosamine Biosynthetic Pathway-coupled HIF-1 Signaling

作者：Chanmee Theerawut; Ontong Pawared; Izumikawa Tomomi; Higashide Miho; Mochizuki Nobutoshi; Chokchaitaweesuk Chatchadawalai; Khansai Manatsanan; Nakajima Kazuki; Kakizaki Ikuko; Kongtawelert Prachya; Taniguchi Naoyuki; Itano Naoki^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291(46): 24105-24120.

DOI：10.1074/jbc.M116.751263

• cancer stem cells
• cell metabolism
• glycolysis
• hyaluronan
• hypoxia-inducible factor (HIF)
• hexosamine biosynthetic pathway

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-1 accumulation and glycolytic program, whereas GFAT1 inhibition significantly decreased HIF-1 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.

• 出版日期2016-11-11