1. Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness.
- Author
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Bogeas A, Morvan-Dubois G, El-Habr EA, Lejeune FX, Defrance M, Narayanan A, Kuranda K, Burel-Vandenbos F, Sayd S, Delaunay V, Dubois LG, Parrinello H, Rialle S, Fabrega S, Idbaih A, Haiech J, Bièche I, Virolle T, Goodhardt M, Chneiweiss H, and Junier MP
- Subjects
- Aged, Animals, Aryl Hydrocarbon Receptor Nuclear Translocator genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Brain Neoplasms genetics, Brain Neoplasms pathology, Cells, Cultured, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Glioblastoma genetics, Glioblastoma pathology, Histone Code, Homeodomain Proteins metabolism, Humans, Mice, Nude, Middle Aged, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Neoplasm Invasiveness physiopathology, Neoplasm Transplantation, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Oligodendrocyte Transcription Factor 2 metabolism, POU Domain Factors metabolism, SOX9 Transcription Factor metabolism, Aryl Hydrocarbon Receptor Nuclear Translocator metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, Brain Neoplasms metabolism, Chromatin metabolism, Glioblastoma metabolism
- Abstract
Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients' glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients' tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness.
- Published
- 2018
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