The transglutaminase 2 gene is aberrantly hypermethylated in glioma

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

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)429-440
Number of pages12
JournalJournal of Neuro-Oncology
Volume101
Issue number3
DOIs
StatePublished - Feb 1 2011

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Dyer, L. M., Schooler, K. P., Ai, L., Klop, C., Qiu, J., Robertson, K. D., & Brown, K. D. (2011). The transglutaminase 2 gene is aberrantly hypermethylated in glioma. Journal of Neuro-Oncology, 101(3), 429-440. https://doi.org/10.1007/s11060-010-0277-7