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.
Jinlong Yin  1  2 ,  Young Taek Oh  2  3 ,  Jeong-Yub Kim  4  5 ,  Sung Soo Kim  1 ,  Eunji Choi  6 ,  Tae Hoon Kim  2 ,  Jun Hee Hong  2 ,  Nakho Chang  3  7 ,  Hee Jin Cho  3  7 ,  Jason K Sa  3  7 ,  Jeong Cheol Kim  4 ,  Hyung Joon Kwon  6 ,  Saewhan Park  1 ,  Weiwei Lin  1 ,  Ichiro Nakano  8  9 ,  Ho-Shin Gwak  1  2 ,  Heon Yoo  1  2 ,  Seung-Hoon Lee  10 ,  Jeongwu Lee  11 ,  Jong Heon Kim  1  12 ,  Soo-Youl Kim  12 ,  Do-Hyun Nam  13  7  14 ,  Myung-Jin Park  15 ,  Jong Bae Park  16  2
Affiliations
  • 1. Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
  • 2. Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
  • 3. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
  • 4. Division of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
  • 5. Department of Pathology, College of Medicine, Korea University, Seoul, Korea.
  • 6. Department of Cancer Control and Policy, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
  • 7. Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
  • 8. Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.
  • 9. UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
  • 10. Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea.
  • 11. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 12. Cancer Cell and Molecular Biology Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea.
  • 13. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea. [email protected] [email protected] [email protected].
  • 14. Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 15. Division of Radiation Cancer Research, Research Center for Radio-Senescence, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. [email protected] [email protected] [email protected].
  • 16. Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea. [email protected] [email protected] [email protected].
PMID: 28754668 DOI: 10.1158/0008-5472.CAN-17-0388
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.

Products