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Title: Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling
Authors: Theerawut Chanmee
Pawared Ontong
Tomomi Izumikawa
Miho Higashide
Nobutoshi Mochizuki
Chatchadawalai Chokchaitaweesuk
Manatsanan Khansai
Kazuki Nakajima
Ikuko Kakizaki
Prachya Kongtawelert
Naoyuki Taniguchi
Naoki Itano
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 11-Nov-2016
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 ratelimiting enzyme, resembled the results of HA overproduction with regard to HIF-1αaccumulation 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.
ISSN: 1083351X
Appears in Collections:CMUL: Journal Articles

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