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

• Published in: Oncogene Vol. 39; no. 15; pp. 3089 - 3101
• Main Authors: Arnold, James M., Gu, Franklin, Ambati, Chandrashekar R., Rasaily, Uttam, Ramirez-Pena, Esmeralda, Joseph, Robiya, Manikkam, Mohan, San Martin, Rebeca, Charles, Christy, Pan, Yinghong, Chatterjee, Sujash S., Den Hollander, Petra, Zhang, Weijie, Nagi, Chandandeep, Sikora, Andrew G., Rowley, David, Putluri, Nagireddy, Zhang, Xiang H.-F., Karanam, Balasubramanyam, Mani, Sendurai A., Sreekumar, Arun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.04.2020; Nature Publishing Group
• Subjects: 101/58; 13/51; 13/89; 14/1; 14/19; 38/39; 38/77; 59/5; 631/45/221; 631/67/1347; 631/67/2327; 631/67/327; 64/60; Acid production; Acids; Animals; Apoptosis; Breast - pathology; Breast cancer; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Chick Embryo; Chorioallantoic Membrane; Development and progression; Disease Progression; Epithelial-Mesenchymal Transition; Extracellular matrix; Extracellular Matrix - pathology; Female; Gene expression; Gene Knockdown Techniques; Genetic aspects; Glucose metabolism; Health aspects; Human Genetics; Humans; Hyaluronic acid; Hyaluronic Acid - biosynthesis; Internal Medicine; Medicine; Medicine & Public Health; Mesenchyme; Metabolism; Metastases; Metastasis; Oncogenes; Oncology; Peroxisome proliferator-activated receptors; PPAR gamma - metabolism; RNA-Seq; Tissue Array Analysis; UDP-glucose 6-dehydrogenase; Uridine Diphosphate Glucose Dehydrogenase - genetics; Uridine Diphosphate Glucose Dehydrogenase - metabolism; Uridine Diphosphate Glucuronic Acid - metabolism; Xenograft Model Antitumor Assays; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0885-4

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.