Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression

Oncogene volume 39, pages 3089–3101 (2020)Cite this article

Subjects

A Correction to this article was published on 25 March 2020

This article has been updated

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Code availability

The source code used is available on https://github.com/SreekumarLab/Publications.

Change history

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    PubMed  Google Scholar 

  2. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    Article  CAS  Google Scholar 

  3. Bhowmik SK, Ramirez-Peña E, Arnold JM, Putluri V, Sphyris N, Michailidis G, et al. EMT-induced metabolite signature identifies poor clinical outcome. Oncotarget 2015;6:42651–60.

    Article  Google Scholar 

  4. Curtis C, Shah SP, Chin S-F, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012;486:346–52.

    Article  CAS  Google Scholar 

  5. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 2006;10:515–27.

    Article  CAS  Google Scholar 

  6. Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31.

    Article  Google Scholar 

  7. Vigetti D, Viola M, Karousou E, De Luca G, Passi A. Metabolic control of hyaluronan synthases. Matrix Biol. 2014;35:8–13.

    Article  CAS  Google Scholar 

  8. Li M, Pathak RR, Lopez-Rivera E, Friedman SL, Aguirre-Ghiso JA, Sikora AG. The in ovo chick chorioallantoic membrane (CAM) assay as an efficient xenograft model of hepatocellular carcinoma. J Vis Exp. 2015;104:52411

    Google Scholar 

  9. Yates TJ, Lopez LE, Lokeshwar SD, Ortiz N, Kallifatidis G, Jordan A, et al. Dietary supplement 4-methylumbelliferone: an effective chemopreventive and therapeutic agent for prostate cancer. J Natl Cancer Inst. 2015;107:djv085

    Article  Google Scholar 

  10. Kultti A, Pasonen-Seppänen S, Jauhiainen M, Rilla KJ, Kärnä R, Pyöriä E, et al. 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res. 2009;315:1914–23.

    Article  CAS  Google Scholar 

  11. Oyinlade O, Wei S, Lal B, Laterra J, Zhu H, Goodwin CR, et al. Targeting UDP-α-d-glucose 6-dehydrogenase inhibits glioblastoma growth and migration. Oncogene 2018;37:2615–29.

    Article  CAS  Google Scholar 

  12. Misra S, Hascall VC, Markwald RR, Ghatak S. Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer. Front Immunol. 2015;6:201.

    Article  Google Scholar 

  13. Saito T, Dai T, Asano R. The hyaluronan synthesis inhibitor 4-methylumbelliferone exhibits antitumor effects against mesenchymal-like canine mammary tumor cells. Oncol Lett. 2013;5:1068–74.

    Article  CAS  Google Scholar 

  14. Sato N, Kohi S, Hirata K, Goggins M. Role of hyaluronan in pancreatic cancer biology and therapy: once again in the spotlight. Cancer Sci. 2016;107:569–75.

    Article  CAS  Google Scholar 

  15. Dong C, Yuan T, Wu Y, Wang Y, Fan TWM, Miriyala S, et al. Loss of FBP1 by snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 2013;23:316–31.

    Article  CAS  Google Scholar 

  16. Lucena MC, Carvalho-Cruz P, Donadio JL, Oliveira IA, de Queiroz RM, Marinho-Carvalho MM, et al. Epithelial mesenchymal transition induces aberrant glycosylation through hexosamine biosynthetic pathway activation. J Biol Chem. 2016;291:12917–29.

    Article  CAS  Google Scholar 

  17. Toole BP. Hyaluronan-CD44 interactions in cancer: paradoxes and possibilities. Clin Cancer Res. 2009;15:7462–8.

    Article  CAS  Google Scholar 

  18. Ricciardelli C, Ween MP, Lokman NA, Tan IA, Pyragius CE, Oehler MK. Chemotherapy-induced hyaluronan production: a novel chemoresistance mechanism in ovarian cancer. BMC Cancer 2013;13:476.

    Article  Google Scholar 

  19. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.

    Article  CAS  Google Scholar 

  20. Hollier BG, Tinnirello AA, Werden SJ, Evans KW, Taube JH, Sarkar TR, et al. FOXC2 expression links epithelial–mesenchymal transition and stem cell properties in breast cancer. Cancer Res. 2013;73:1981–92.

    Article  CAS  Google Scholar 

  21. Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, et al. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells 2010;28:1435–45.

    Article  CAS  Google Scholar 

  22. Putluri N, Shojaie A, Vasu VT, Vareed SK, Nalluri S, Putluri V, et al. Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression. Cancer Res. 2011;71:7376–86.

    Article  CAS  Google Scholar 

  23. Gentleman R. Bioinformatics and computational biology solutions using R and Bioconductor [Internet]. New York: Springer Science+Business Media; 2005 [cited 15 Apr 2019].

  24. Putluri N, Maity S, Kommagani R, Kommangani R, Creighton CJ, Putluri V, et al. Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance. Neoplasia. 2014;16:390–402.

    Article  CAS  Google Scholar 

  25. Dasgupta S, Putluri N, Long W, Zhang B, Wang J, Kaushik AK, et al. Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis. J Clin Investig. 2015;125:1174–88.

    Article  Google Scholar 

  26. Marshall J. Transwell(®) invasion assays. Methods Mol Biol. 2011;769:97–110.

    Article  CAS  Google Scholar 

  27. Werden SJ, Sphyris N, Sarkar TR, Paranjape AN, LaBaff AM, Taube JH, et al. Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth. Oncogene 2016;35:5977–88.

    Article  CAS  Google Scholar 

  28. van der Horst EH, Leupold JH, Schubbert R, Ullrich A, Allgayer H. TaqMan-based quantification of invasive cells in the chick embryo metastasis assay. BioTechniques. 2004;37:940–2. 944, 946

    Article  Google Scholar 

  29. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–7.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. These authors contributed equally: James M. Arnold, Franklin Gu

Authors and Affiliations

  1. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    James M. Arnold, Franklin Gu, Christy Charles & Arun Sreekumar

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    James M. Arnold, Franklin Gu, Uttam Rasaily, Mohan Manikkam, Rebeca San Martin, Christy Charles, Weijie Zhang, David Rowley, Nagireddy Putluri, Xiang H.-F. Zhang & Arun Sreekumar

  3. Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, 77030, USA

    James M. Arnold, Franklin Gu, Chandrashekar R. Ambati, Uttam Rasaily, Christy Charles, Nagireddy Putluri & Arun Sreekumar

  4. Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Esmeralda Ramirez-Pena, Robiya Joseph, Petra Den Hollander & Sendurai A. Mani

  5. Division of Cancer Prevention, National Cancer Institute, Rockville, MD, 20850, USA

    Esmeralda Ramirez-Pena

  6. Seq-N-Edit Core, Department of Biology and Biochemistry, University of Houston, Houston, TX, 77004, USA

    Yinghong Pan & Sujash S. Chatterjee

  7. UPMC Genome Center, Pittsburgh, PA, 15232, USA

    Yinghong Pan

  8. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Weijie Zhang & Xiang H.-F. Zhang

  9. Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Weijie Zhang

  10. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA

    Chandandeep Nagi

  11. Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, 77030, USA

    Andrew G. Sikora

  12. Department of Biology and Cancer Research, Tuskegee University, Tuskegee, AL, 36088, USA

    Balasubramanyam Karanam

Authors
  1. James M. Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Franklin Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chandrashekar R. Ambati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Uttam Rasaily
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Esmeralda Ramirez-Pena
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robiya Joseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohan Manikkam
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rebeca San Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christy Charles
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yinghong Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sujash S. Chatterjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Petra Den Hollander
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Weijie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chandandeep Nagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Andrew G. Sikora
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David Rowley
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Nagireddy Putluri
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xiang H.-F. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Balasubramanyam Karanam
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Sendurai A. Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Arun Sreekumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arun Sreekumar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arnold, J.M., Gu, F., Ambati, C.R. et al. UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression. Oncogene 39, 3089–3101 (2020). https://doi.org/10.1038/s41388-019-0885-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0885-4

This article is cited by

Search

Advanced search

Quick links