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/EBPb, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-kB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPb 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.
Bibliographical noteFunding Information:
This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1410290, NCC-1510061), Basic Science Research
Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015H1D3A1036090, NRF-2015R1A2A1A15054865,NRF-2015M3A9D9067485,NRF-2017R1A2B4011741, and NRF-2015R1C1A1A01054963), the Korea Institute of Radiological and Medical Science (KIRAMS), funded by the Ministry of Science, ICT and Future Planning, Republic of Korea (1711045557, 1711045538, 1711045554/50531-2017), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea, HI14C3418.
ASJC Scopus subject areas
- Cancer Research