Abstract
UDP-glucose 6-dehydrogenase (UGDH) produces UDP-α-d-glucuronic acid, the precursors for glycosaminoglycans (GAGs) and proteoglycans of the extracellular matrix. Elevated GAG formation has been implicated in a variety of human diseases, including glioblastoma (GBM). In our previous study, we found that Krüppel-like factor 4 (KLF4) promotes GBM cell migration by binding to methylated DNA, mainly methylated CpGs (mCpG) and transactivating gene expression. We identified UDGH as one of the downstream targets of KLF4–mCpG binding activity. In this study, we show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins such as tenascin C, brevican. Our studies demonstrate a novel DNA methylation-dependent UGDH upregulation by KLF4. Developing UGDH antagonists to decrease the synthesis of extracellular matrix components will be a useful strategy for GBM therapy.
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Acknowledgements
We thank Dr. H Lopez-Bertoni for technical expertise.
Fundng
This work was supported by grants from NIH R01NS091165 (to SX), NIH R01 NS096754 (to JL), NS076759 (to JL), NIH GM111514 (to HZ), NIH R01 GM111514 (to HZ), NIH R33CA186790 (to HZ), NIH U54 HG006434 (to HZ), NIH U24 CA160036 (to HZ), Ford Foundation pre-doctoral fellowship program (to OO) and NIH T32 GM007445 (to OO), NIH/NINDS K12 Physician Scientist Award, Burroughs Wellcome Fund, and Duke SPORE CEP Award (to CRG).
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Oyinlade, O., Wei, S., Lal, B. et al. Targeting UDP-α-d-glucose 6-dehydrogenase inhibits glioblastoma growth and migration. Oncogene 37, 2615–2629 (2018). https://doi.org/10.1038/s41388-018-0138-y
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DOI: https://doi.org/10.1038/s41388-018-0138-y
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