ARNT2 repression disrupts neuronal identity and promotes glioblastoma growth
Yi-Heng Hao1, Nofit Borenstein-Auerbach1, Anthony Grichuk1
1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Abstract:
Tumor initiation and progression frequently involve oncogenic programs that favor proliferation at the expense of lineage commitment and differentiation. Here, we identify a MYC-driven mechanism that suppresses neuronal identity in glioblastoma (GBM) through repression of the transcription factor aryl hydrocarbon receptor nuclear translocator 2 (ARNT2). ARNT2 is highly expressed in the brain, cerebellum, and iPSC-derived neurons but is markedly reduced in GBM tumors and cell lines, where its loss correlates with higher tumor grade and poor survival. Mechanistically, MYC represses ARNT2 expression, and ARNT2 loss results in reduced expression of neuronal and glial identity genes. Although ARNT2 depletion does not alter GBM cell proliferation in vitro, it significantly enhances tumor growth and lipid metabolic remodeling in vivo. Conversely, ectopic ARNT2 expression suppresses tumor burden in both subcutaneous and orthotopic GBM xenograft models and promotes features of neuronal differentiation. Together, these findings identify ARNT2 as a tumor suppressor in GBM and establish MYC-mediated repression of ARNT2 as a critical mechanism by which GBM maintains a proliferative, undifferentiated, stem-like state.
Insights
MYC oncogene suppresses neuronal identity in glioblastoma (GBM) by reducing aryl hydrocarbon receptor nuclear translocator 2 (ARNT2). Loss of ARNT2 promotes GBM tumor growth and maintains its undifferentiated state.
Area of Science:
- Oncology
- Neuroscience
- Molecular Biology
Background:
- Glioblastoma (GBM) progression often involves oncogenic programs that prioritize proliferation over cell differentiation.
- Maintaining a proliferative, undifferentiated state is a hallmark of aggressive GBM tumors.
Purpose of the Study:
- To identify MYC-driven mechanisms that suppress neuronal identity in GBM.
- To investigate the role of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) in GBM pathogenesis.
Main Methods:
- Analysis of ARNT2 expression in GBM tumors and cell lines.
- Investigating the regulatory relationship between MYC and ARNT2.
- Assessing the impact of ARNT2 depletion and ectopic expression on GBM cell behavior in vitro and in vivo.
- Utilizing subcutaneous and orthotopic GBM xenograft models.
Main Results:
- ARNT2 expression is significantly reduced in GBM, correlating with higher tumor grade and poorer patient survival.
- MYC directly represses ARNT2 expression, leading to decreased expression of neuronal and glial identity genes.
- ARNT2 loss enhances GBM tumor growth and alters lipid metabolism in vivo, while its ectopic expression suppresses tumor burden and promotes neuronal differentiation.
Conclusions:
- ARNT2 acts as a tumor suppressor in GBM.
- MYC-mediated repression of ARNT2 is a key mechanism enabling GBM to maintain a proliferative, stem-like, and undifferentiated state.
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