UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression.
Animals
Breast
/ pathology
Breast Neoplasms
/ pathology
Cell Line, Tumor
Chick Embryo
Chorioallantoic Membrane
Disease Progression
Epithelial-Mesenchymal Transition
Extracellular Matrix
/ pathology
Female
Gene Knockdown Techniques
Humans
Hyaluronic Acid
/ biosynthesis
PPAR gamma
/ metabolism
RNA-Seq
Tissue Array Analysis
Uridine Diphosphate Glucose Dehydrogenase
/ genetics
Uridine Diphosphate Glucuronic Acid
/ metabolism
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
02
11
2018
accepted:
03
07
2019
revised:
25
04
2019
pubmed:
17
7
2019
medline:
15
12
2020
entrez:
17
7
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31308490
doi: 10.1038/s41388-019-0885-4
pii: 10.1038/s41388-019-0885-4
pmc: PMC6960374
mid: NIHMS1533642
doi:
Substances chimiques
PPAR gamma
0
PPARG protein, human
0
Uridine Diphosphate Glucuronic Acid
2616-64-0
Hyaluronic Acid
9004-61-9
UGDH protein, human
EC 1.1.1.22
Uridine Diphosphate Glucose Dehydrogenase
EC 1.1.1.22
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3089-3101Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220297
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA179674
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200970
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA186784
Pays : United States
Commentaires et corrections
Type : ErratumIn
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