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Targeting UDP-α-d-glucose 6-dehydrogenase inhibits glioblastoma growth and migration

Oncogene volume 37, pages 2615–2629 (2018)Cite this article

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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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References

  1. Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, et al. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009;18:1061–83.

    Article  CAS  PubMed  Google Scholar 

  2. Batash R, Asna N, Schaffer P, Francis N, Schaffer M. Glioblastoma multiforme, diagnosis and treatment; recent literature review. Curr Med Chem. 2017;24:3002–9.

    Article  CAS  PubMed  Google Scholar 

  3. Marzenna W, Rojiani MV. Extracellular matrix microenvironment in glioma progression. In: Ghosh A, editor. Glioma - Exploring Its Biology and Practical Relevance. InTech; 2011;(Chap 12):257–284.

  4. Venning FA, Wullkopf L, Erler JT. Targeting ECM disrupts cancer progression. Front Oncol. 2015;5:224.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, et al. Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J. 2012;279:1177–97.

    Article  CAS  PubMed  Google Scholar 

  7. Wan J, Su Y, Song Q, Tung B, Oyinlade O, Liu S, et al. Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration. eLife. 2017;6:e20068.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hu S, Wan J, Su Y, Song Q, Zeng Y, Nguyen HN, et al. DNA methylation presents distinct binding sites for human transcription factors. eLife. 2013;2:e00726.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Egger S, Chaikuad A, Kavanagh KL, Oppermann U, Nidetzky B. UDP-glucose dehydrogenase: structure and function of a potential drug target. Biochem Soc Trans. 2010;38:1378–85.

    Article  CAS  PubMed  Google Scholar 

  10. Clarkin CE, Allen S, Kuiper NJ, Wheeler BT, Wheeler-Jones CP, Pitsillides AA. Regulation of UDP-glucose dehydrogenase is sufficient to modulate hyaluronan production and release, control sulfated GAG synthesis, and promote chondrogenesis. J Cell Physiol. 2011;226:749–61.

    Article  CAS  PubMed  Google Scholar 

  11. Wen Y, Li J, Wang L, Tie K, Magdalou J, Chen L, et al. UDP-glucose dehydrogenase modulates proteoglycan synthesis in articular chondrocytes: its possible involvement and regulation in osteoarthritis. Arthritis Res Ther. 2014;16:484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4:528–39.

    Article  CAS  PubMed  Google Scholar 

  13. Park JB, Kwak H-J, Lee S-H. Role of hyaluronan in glioma invasion. Cell Adhes Migr. 2008;2:202–7.

    Article  Google Scholar 

  14. Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol. 2011;3:a005058

    Article  PubMed  PubMed Central  Google Scholar 

  15. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.

    Article  CAS  PubMed  Google Scholar 

  16. Yu F, Li J, Chen H, Fu J, Ray S, Huang S, et al. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene. 2011;30:2161–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tilghman J, Wu H, Sang Y, Shi X, Guerrero-Cazares H, Quinones-Hinojosa A, et al. HMMR maintains the stemness and tumorigenicity of glioblastoma stem-like cells. Cancer Res. 2014;74:3168–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ying M, Tilghman J, Wei Y, Guerrero-Cazares H, Quinones-Hinojosa A, Ji H, et al. Kruppel-like factor-9 (KLF9) inhibits glioblastoma stemness through global transcription repression and integrin alpha6 inhibition. J Biol Chem. 2014;289:32742–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu Y, Richard JP, Wang SD, Rath P, Laterra J, Xia S. Regulation of glioblastoma multiforme stem-like cells by inhibitor of DNA binding proteins and oligodendroglial lineage-associated transcription factors. Cancer Sci. 2012;103:1028–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rath P, Lal B, Ajala O, Li Y, Xia S, Kim J, et al. In vivo c-Met pathway inhibition depletes human glioma xenografts of tumor-propagating stem-like cells. Transl Oncol. 2013;6:104–11.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Xia S, Lal B, Tung B, Wang S, Goodwin CR, Laterra J. Tumor microenvironment tenascin-C promotes glioblastoma invasion and negatively regulates tumor proliferation. Neuro-Oncology. 2016;18:507–17.

    Article  CAS  PubMed  Google Scholar 

  22. Barbosa I, Garcia S, Barbier-Chassefière V, Caruelle J-P, Martelly I, Papy-García D. Improved and simple micro assay for sulfated glycosaminoglycans quantification in biological extracts and its use in skin and muscle tissue studies. Glycobiology. 2003;13:647–53.

    Article  CAS  PubMed  Google Scholar 

  23. Wang SD, Rath P, Lal B, Richard JP, Li Y, Goodwin CR, et al. EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene. 2012;31:5132–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reznik TE, Sang Y, Ma Y, Abounader R, Rosen EM, Xia S, et al. Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res. 2008;6:139–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ. Proteoglycans and their roles in brain cancer. FEBS J. 2013;280:2399–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nutt CL, Zerillo CA, Kelly GM, Hockfield S. Brain enriched hyaluronan binding (BEHAB)/brevican increases aggressiveness of CNS-1 gliomas in Lewis rats. Cancer Res. 2001;61:7056–9.

    CAS  PubMed  Google Scholar 

  27. Craig JM, Bickmore WA. The distribution of CpG islands in mammalian chromosomes. Nat Genet. 1994;7:376–82.

    Article  CAS  PubMed  Google Scholar 

  28. Medvedeva YA, Khamis AM, Kulakovskiy IV, Ba-Alawi W, Bhuyan MSI, Kawaji H, et al. Effects of cytosine methylation on transcription factor binding sites. BMC Genom. 2014;15:119.

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA

    Olutobi Oyinlade, Shuang Wei, Bachchu Lal, John Laterra, Shuyan Wang, Ding Ma & Shuli Xia

  2. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Olutobi Oyinlade & Heng Zhu

  3. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Shuang Wei, Bachchu Lal, John Laterra, Shuyan Wang, Ding Ma & Shuli Xia

  4. Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China

    Shuang Wei

  5. Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    John Laterra

  6. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    John Laterra

  7. High throughput Biology Center, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Heng Zhu

  8. Department of Neurosurgery, Duke University Medical Center, Durham, NC, 27710, USA

    C. Rory Goodwin

  9. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Jun Wan

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  1. Olutobi Oyinlade
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Correspondence to Shuli Xia.

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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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