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The transglutaminase 2 gene is aberrantly hypermethylated in glioma

Journal of Neuro-Oncology volume 101, pages 429–440 (2011)Cite this article

Abstract

Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein/protein crosslinking. Because extracellular TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type. Because tumor invasiveness is a primary determinant of brain tumor aggressiveness, we sought to determine if TGM2 is targeted for epigenetic silencing in glioma. Analysis of TGM2 gene methylation in a panel of cultured human glioma cells indicated that the 5′ flanking region of the TGM2 gene is hypermethylated and that this feature is associated with reduced TG2 expression as judged by immunoblotting. Further, culturing glioma cells in the presence of the global DNA demethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor Trichostatin A resulted in re-expression of TG2 in these lines. In primary brain tumors we observed that the TGM2 promoter is commonly hypermethylated and that this feature is a cancer-associated phenomenon. Using publically available databases, TG2 expression in gliomas was found to vary widely, with many tumors showing overexpression or underexpression of this gene. Since overexpression of TG2 leads to resistance to doxorubicin through the ectopic activation of NFκB, we sought to examine the effects of recombinant TG2 expression in glioma cells treated with commonly used brain tumor therapeutics. We observed that in addition to doxorubicin, TG2 expression drove resistance to CCNU; however, TG2 expression did not alter sensitivity to other drugs tested. Finally, a catalytically null mutant of TG2 was also able to support doxorubicin resistance in glioma cells indicating that transglutaminase activity is not necessary for the resistance phenotype.

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Acknowledgements

The authors are grateful to Mr. Jonathan Green for technical expertise and the Florida Center for Brain Tumor Research (FCBTR) for providing access to clinical samples. Work was supported by a grant (RO1 CA102289) to KDB.

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Author notes

  1. Keith D. Robertson

    Present address: Department of Biochemistry and Molecular Biology and the MCG Cancer Center, Medical College of Georgia, Augusta, GA, USA

Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Box 100245, Gainesville, FL, 32610-0245, USA

    Lisa M. Dyer, Lingbao Ai, Keith D. Robertson & Kevin D. Brown

  2. Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA

    Kevin P. Schooler

  3. Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA

    Jingxin Qiu

  4. UF-Shands Cancer Center Program in Genetics, Epigenetics and Tumor Virology, University of Florida College of Medicine, Gainesville, FL, USA

    Lisa M. Dyer, Lingbao Ai, Corinne Klop, Jingxin Qiu, Keith D. Robertson & Kevin D. Brown

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  1. Lisa M. Dyer
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  2. Kevin P. Schooler
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Correspondence to Kevin D. Brown.

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Dyer, L.M., Schooler, K.P., Ai, L. et al. The transglutaminase 2 gene is aberrantly hypermethylated in glioma. J Neurooncol 101, 429–440 (2011). https://doi.org/10.1007/s11060-010-0277-7

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  • DOI: https://doi.org/10.1007/s11060-010-0277-7

Keywords

  • Glioma
  • Epigenetic silencing
  • Extra cellular matrix
  • Tumor invasiveness
  • Drug resistance