title: Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas.
abstract: We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM), the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N = 414), Sox2 gene amplification (8.5%; N = 492), and Sox 2 promoter hypomethylation (100%; N = 258), suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs) and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in established glioma cells was not sufficient to support self-renewal, suggesting that additional factors are required. Furthermore, we observed that ectopic Sox2 expression was sufficient to induce invasion and migration of glioma cells, and knockdown experiments demonstrated that Sox2 was essential for maintaining these properties. Altogether, our data underscore the importance of a pleiotropic role of Sox2 and suggest that it could be used as a therapeutic target in GBM.
authors: Department of Neuro-oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors: Marta M
authors: MM
authors: Alonso
authors: Ricardo
authors: R
authors: Diez-Valle
authors: Lorea
authors: L
authors: Manterola
authors: Angel
authors: A
authors: Rubio
authors: Dan
authors: D
authors: Liu
authors: Nahir
authors: N
authors: Cortes-Santiago
authors: Leire
authors: L
authors: Urquiza
authors: Patricia
authors: P
authors: Jauregi
authors: Adolfo
authors: A
authors: Lopez de Munain
authors: Nicolás
authors: N
authors: Sampron
authors: Ander
authors: A
authors: Aramburu
authors: Sonia
authors: S
authors: Tejada-Solís
authors: Carmen
authors: C
authors: Vicente
authors: María D
authors: MD
authors: Odero
authors: Eva
authors: E
authors: Bandrés
authors: Jesús
authors: J
authors: García-Foncillas
authors: Miguel A
authors: MA
authors: Idoate
authors: Frederick F
authors: FF
authors: Lang
authors: Juan
authors: J
authors: Fueyo
authors: Candelaria
authors: C
authors: Gomez-Manzano
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D057890:Epigenomics; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D001374:Azacitidine