Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPβ Signaling

Cancer Res. 2017 Sep 15;77(18):4973-4984. doi: 10.1158/0008-5472.CAN-17-0388. Epub 2017 Jul 28.

Abstract

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. ©2017 AACR.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Proliferation
  • Cell Transdifferentiation
  • Female
  • GTP-Binding Proteins / antagonists & inhibitors*
  • GTP-Binding Proteins / metabolism
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology*
  • Humans
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases / antagonists & inhibitors*
  • Transglutaminases / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • CCAAT-Enhancer-Binding Protein-beta
  • TGM2 protein, human
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins