Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24105-24120
Number of pages16
JournalJournal of Biological Chemistry
Volume291
Issue number46
DOIs
Publication statusPublished - 11-11-2016

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Hexosamines
Biosynthetic Pathways
Hyaluronic Acid
Stem cells
Neoplastic Stem Cells
Cells
Breast Neoplasms
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
Neoplasms
Stem Cells
Metabolomics
Glycolysis
Enzymes
Isotopes
Plastics
Mass Spectrometry
Mass spectrometry
Fluxes
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Chanmee, Theerawut ; Ontong, Pawared ; Izumikawa, Tomomi ; Higashide, Miho ; Mochizuki, Nobutoshi ; Chokchaitaweesuk, Chatchadawalai ; Khansai, Manatsanan ; Nakajima, Kazuki ; Kakizaki, Ikuko ; Kongtawelert, Prachya ; Taniguchi, Naoyuki ; Itano, Naoki. / Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 46. pp. 24105-24120.
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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",
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.",
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Chanmee, T, Ontong, P, Izumikawa, T, Higashide, M, Mochizuki, N, Chokchaitaweesuk, C, Khansai, M, Nakajima, K, Kakizaki, I, Kongtawelert, P, Taniguchi, N & Itano, N 2016, 'Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling', Journal of Biological Chemistry, vol. 291, no. 46, pp. 24105-24120. https://doi.org/10.1074/jbc.M116.751263

Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling. / Chanmee, Theerawut; Ontong, Pawared; Izumikawa, Tomomi; Higashide, Miho; Mochizuki, Nobutoshi; Chokchaitaweesuk, Chatchadawalai; Khansai, Manatsanan; Nakajima, Kazuki; Kakizaki, Ikuko; Kongtawelert, Prachya; Taniguchi, Naoyuki; Itano, Naoki.

In: Journal of Biological Chemistry, Vol. 291, No. 46, 11.11.2016, p. 24105-24120.

Research output: Contribution to journalArticle

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T1 - Hyaluronan production regulates metabolic and cancer stem-like properties of breast cancer cells via hexosamine biosynthetic pathway-coupled HIF-1 signaling

AU - Chanmee, Theerawut

AU - Ontong, Pawared

AU - Izumikawa, Tomomi

AU - Higashide, Miho

AU - Mochizuki, Nobutoshi

AU - Chokchaitaweesuk, Chatchadawalai

AU - Khansai, Manatsanan

AU - Nakajima, Kazuki

AU - Kakizaki, Ikuko

AU - Kongtawelert, Prachya

AU - Taniguchi, Naoyuki

AU - Itano, Naoki

PY - 2016/11/11

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N2 - 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.

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