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

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

Yin J1,2, Oh YT2,3, Kim JY4,5, Kim SS1, Choi E6, Kim TH2, Hong JH2, Chang N3,7, Cho HJ3,7, Sa JK3,7, Kim JC4, Kwon HJ6, Park S1, Lin W1, Nakano I8,9, Gwak HS1,2, Yoo H1,2, Lee SH10, Lee J11, Kim JH1,12, Kim SY12, Nam DH13,7,14, Park MJ15, Park JB16,2.

Author information

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. jbp@ncc.re.kr mjpark@kcch.re.kr nsnam@skku.edu.
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. jbp@ncc.re.kr mjpark@kcch.re.kr nsnam@skku.edu.
16
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea. jbp@ncc.re.kr mjpark@kcch.re.kr nsnam@skku.edu.

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.

PMID:
28754668
DOI:
10.1158/0008-5472.CAN-17-0388
[Indexed for MEDLINE]
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