TY - JOUR
T1 - UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression
AU - Arnold, James M.
AU - Gu, Franklin
AU - Ambati, Chandrashekar R.
AU - Rasaily, Uttam
AU - Ramirez-Pena, Esmeralda
AU - Joseph, Robiya
AU - Manikkam, Mohan
AU - San Martin, Rebeca
AU - Charles, Christy
AU - Pan, Yinghong
AU - Chatterjee, Sujash S.
AU - Den Hollander, Petra
AU - Zhang, Weijie
AU - Nagi, Chandandeep
AU - Sikora, Andrew G.
AU - Rowley, David
AU - Putluri, Nagireddy
AU - Zhang, Xiang H.F.
AU - Karanam, Balasubramanyam
AU - Mani, Sendurai A.
AU - Sreekumar, Arun
N1 - Funding Information:
Acknowledgements Thanks to Mariana Villanueva MS and Ravi Pathak Ph.D. M.B.A, in the Baylor College of Medicine Advanced in vivo Models Core for assistance with chicken chorioallantoic membrane assays. This research was partially funded by National Cancer Institute grant numbers U01CA179674-01A1 (AS), National Science Foundation NSF PHY-1605817 (SAM) NCI R01CA200970 (SAM), P30CA125123 Metabolomics Shared Resources (AS), R01CA220297 (NP), and partially supported by P50CA186784 to C. K. Osborne; CPRIT grant numbers RP170005 to the Proteomics and Metabolomics Core Facility (AS and NP); CPRIT Core Facilities Support Grant RP170691 (ML and AS); funds from the Alkek Center for Molecular Discovery (AS) and Agilent Technologies Center for Excellence in Mass Spectrometry (AS); UH Division of Research, UH College of Natural Sciences and Mathematics, and Department of Biology & Biochemistry, NRUF MINOR CORE 17 Grant to support Seq-N-Edit Core.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/4/9
Y1 - 2020/4/9
N2 - 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.
AB - 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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U2 - 10.1038/s41388-019-0885-4
DO - 10.1038/s41388-019-0885-4
M3 - Article
C2 - 31308490
AN - SCOPUS:85069541261
SN - 0950-9232
VL - 39
SP - 3089
EP - 3101
JO - Oncogene
JF - Oncogene
IS - 15
ER -