CRISPR/Cas9 Deletion of SOX2 Regulatory Region 2 (SRR2) Decreases SOX2 Malignant Activity in Glioblastoma
Open Access
Abstract
SOX2 is a transcription factor associated with stem cell activity in several tissues. In cancer, SOX2 expression is increased in samples from several malignancies, including glioblastoma, and high SOX2 levels are associated with the population of tumor-initiating cells and with poor patient outcome. Therefore, understanding how SOX2 is regulated in cancer cells is relevant to tackle tumorigenesis. The SOX2 regulatory region 2(SRR2) is located downstream of the SOX2 coding region and mediates SOX2 expression in embryonic and adult stem cells. In this study, we deleted SRR2 using CRISPR/Cas9 in glioblastoma cells. Importantly, SRR2-deleted glioblastoma cells presented reduced SOX2 expression and decreased proliferative activity and self-renewal capacity in vitro. In line with these results, SRR2-deleted glioblastoma cells displayed decreased tumor initiation and growth in vivo. These effects correlated with an elevation of p21CIP1 cell cycle and p27KIP1 quiescence regulators. In conclusion, our data reveal that SRR2 deletion halts malignant activity of SOX2 and confirms that the SRR2 enhancer regulates SOX2 expression in cancer.Keywords
Funding Information
- Instituto de Salud Carlos III (PI16/01580, PI19/01355)
This publication has 31 references indexed in Scilit:
- SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cellsOncogenesis, 2013
- p27Kip1 Directly Represses Sox2 during Embryonic Stem Cell DifferentiationCell Stem Cell, 2012
- Genetic and Epigenetic Modifications of Sox2 Contribute to the Invasive Phenotype of Malignant GliomasPLOS ONE, 2011
- Identification of a SOX2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profileNeuro-Oncology, 2011
- Sox2 expression in breast tumours and activation in breast cancer stem cellsOncogene, 2011
- Sox2 regulatory region 2 sequence works as a DNA nuclear targeting sequence enhancing the efficiency of an exogenous gene expression in ES cellsBiochemical and Biophysical Research Communications, 2010
- SOX2 Silencing in Glioblastoma Tumor-Initiating Cells Causes Stop of Proliferation and Loss of TumorigenicityStem Cells, 2009
- Epigenetic modifications of SOX2 enhancers, SRR1 and SRR2, correlate with in vitro neural differentiationJournal of Neuroscience Research, 2008
- The Sox-2 Regulatory Regions Display Their Activities in Two Distinct Types of Multipotent Stem CellsMolecular and Cellular Biology, 2004
- Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complexNucleic Acids Research, 2002