Abstract
Simple SummaryUnderstanding how SOX2, a major driver of cancer stem cells, is regulated in cancer cells is relevant to tackle tumorigenesis. In this study, we deleted the SRR2 regulatory region in glioblastoma cells. Our data confirm that the SRR2 enhancer regulates SOX2 expression in cancer and reveal that SRR2 deletion halts malignant activity of SOX2.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.
Highlights
SOX2 construct (SOX2) is a member of the SOX family of high mobility group (HMG) box transcription factors, and plays an important role in the maintenance of embryonic stem cell pluripotency and progenitor identity during embryogenesis and in adulthood [1]
Since the association of p21CIP1 and p27KIP1 partly mediates the effect of SOX2 regulatory region 2 (SRR2) on SOX2 repression in several cell types [20], we studied the expression of p21CIP1 and p27KIP1 in glioma cell lines and biopsies
Glioma cell lines cultured under stem cell media grow as oncospheres, which express a striking elevation of SOX2 levels [15]
Summary
SOX2 is a member of the SOX family of high mobility group (HMG) box transcription factors, and plays an important role in the maintenance of embryonic stem cell pluripotency and progenitor identity during embryogenesis and in adulthood [1]. In the embryonic central nervous system, SOX2 is expressed throughout the neural tube during early stages of neurogenesis and in progenitors as development progresses. It is required for neural stem cell (NSC) activity in the adult. Several studies describe how SOX2 expression is elevated in a large proportion of cancers, including brain tumors such as glioblastoma (GBM) [2,3,4,5,6]. GBM is the most common malignant primary brain tumor in adults. The average survival of patients diagnosed with GBM is around 15 months [7]. GBMs are notorious for their resistance to therapy, which has been linked to genetic and cellular heterogeneity [8]
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