UDP-glucose 6-dehydrogenase knockout impairs migration and decreases in vivo metastatic ability of breast cancer cells

• Published in: Cancer letters Vol. 492; pp. 21 - 30
• Main Authors: Teoh, Shao Thing, Ogrodzinski, Martin P., Lunt, Sophia Y.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.11.2020; Elsevier Limited
• Subjects: Acids; Animals; Biosynthesis; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Cell migration; Cell Movement; Cell proliferation; Cell surface; CRISPR; Epithelial-Mesenchymal Transition; Female; Gene expression; Glucose; Glycosylation; Humans; Lung Neoplasms - secondary; Medical prognosis; Metabolism; Metabolites; Metastases; Metastasis; Mice; Signal transduction; Survival analysis; UDP-glucose 6-dehydrogenase; Uridine Diphosphate Glucose Dehydrogenase - physiology; Uridine Diphosphate Glucuronic Acid - biosynthesis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.07.031

Dysregulated metabolism is a hallmark of cancer that supports tumor growth and metastasis. One understudied aspect of cancer metabolism is altered nucleotide sugar biosynthesis, which drives aberrant cell surface glycosylation known to support various aspects of cancer cell behavior including migration and signaling. We examined clinical association of nucleotide sugar pathway gene expression and found that UGDH, encoding UDP-glucose 6-dehydrogenase which catalyzes production of UDP-glucuronate, is associated with worse breast cancer patient survival. Knocking out the mouse homolog Ugdh in highly-metastatic 6DT1 breast cancer cells impaired migration ability without affecting in vitro proliferation. Further, Ugdh-KO resulted in significantly decreased metastatic capacity in vivo when the cells were orthotopically injected in syngeneic mice. Our experiments show that UDP-glucuronate biosynthesis is critical for metastasis in a mouse model of breast cancer. •High UGDH expression correlates with worse breast cancer patient survival.•Knockout of Ugdh in mouse breast cancer cells impacts their migration.•Ugdh-KO tumors are significantly less metastatic in vivo.•Decreased migration and metastasis of Ugdh-KO are not due to impaired EMT.