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UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression.

Oncogene. 2020 Apr;39(15):3089-3101. Epub 2019 Jul 15
James M Arnold 1 , Franklin Gu 1 , Chandrashekar R Ambati 1 , Uttam Rasaily 1 , Esmeralda Ramirez-Pena 2 , Robiya Joseph 3 , Mohan Manikkam 4 , Rebeca San Martin 4 , Christy Charles 1 , Yinghong Pan 5 , Sujash S Chatterjee 6 , Petra Den Hollander 3 , Weijie Zhang 7 , Chandandeep Nagi 8 , Andrew G Sikora 9 , David Rowley 4 , Nagireddy Putluri 1 , Xiang H-F Zhang 10 , Balasubramanyam Karanam 11 , Sendurai A Mani 3 , Arun Sreekumar 12
James M Arnold 1 , Franklin Gu 1 , Chandrashekar R Ambati 1 , Uttam Rasaily 1 , Esmeralda Ramirez-Pena 2 , Robiya Joseph 3 , Mohan Manikkam 4 , Rebeca San Martin 4 , Christy Charles 1 , Yinghong Pan 5 , Sujash S Chatterjee 6 , Petra Den Hollander 3 , Weijie Zhang 7 , Chandandeep Nagi 8 , Andrew G Sikora 9 , David Rowley 4 , Nagireddy Putluri 1 , Xiang H-F Zhang 10 , Balasubramanyam Karanam 11 , Sendurai A Mani 3 , Arun Sreekumar 12
+ et al

[No authors listed]

Author information
  • 1 Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 2 Division of Cancer Prevention, National Cancer Institute, Rockville, MD, 20850, USA.
  • 3 Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
  • 5 UPMC Genome Center, Pittsburgh, PA, 15232, USA.
  • 6 Seq-N-Edit Core, Department of Biology and Biochemistry, University of Houston, Houston, TX, 77004, USA.
  • 7 Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
  • 8 Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 9 Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 10 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
  • 11 Department of Biology and Cancer Research, Tuskegee University, Tuskegee, AL, 36088, USA.
  • 12 Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, 77030, USA. sreekuma@bcm.edu.

摘要

An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.

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