Elevating SOX2 Levels Deleteriously Affects the Growth of Medulloblastoma and Glioblastoma Cells

Abstract

Medulloblastomas and glioblastomas are devastating tumors that respond poorly to treatment. These tumors have been shown to express SOX2 and overexpression of SOX2 has been correlated with poor prognosis. Although knockdown of SOX2 impairs the growth and tumorigenicity of brain tumor cells, it was unclear how elevating SOX2 levels would affect their fate. Interestingly, studies conducted with neural stem cells have shown that small increases or decreases in the level of this transcription factor significantly alter their fate. Here, we report that elevating SOX2 3-fold above endogenous levels in U87 and U118 glioblastoma, and DAOY medulloblastoma cells significantly impairs their ability to proliferate. We extended these findings and determined that elevating SOX2 in DAOY cells remodels their cell-cycle profile by increasing the proportion of cells in the G1-compartment, and induces the expression of genes associated with differentiation. Furthermore, we show that elevating SOX2 leads to a dramatic induction of CD133 expression in DAOY cells, yet inhibits the ability of both CD133+ and CD133− cells to form neurospheres. Together, these findings argue that SOX2 levels must be carefully controlled in glioblastomas and medulloblastomas to maintain their fate. Equally important, our data suggests that increases in the expression of SOX2 during brain tumor progression are likely to be linked closely with changes in other critical genes that work in concert with SOX2 to enhance the tumorigenicity of brain tumors. Importantly, we demonstrate that this is also likely to be true for other cancers that express SOX2. Moreover, these studies demonstrate the advantage of using inducible promoters to study the effects of SOX2 elevation, as compared to gene expression systems that rely on constitutive expression.

Curcumin induces glioma stem-like cell formation

“…Sox4, Sox2, and Oct4 were the three genes responsible for the stemness retained in glioma stem cells, which were overexpressed in stem cells, and reduction of which induced stem cell differentiation [11][12][13]. In this study, our results showed that Sox4, Sox2, and Oct4 were overexpressed in the stem-like spheres, which were induced by curcumin.…”

Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma

“…For example, stable expression of the transcription factor SOX2 in neoplastic cells enriches a subpopulation with enhanced growth, [13][14][15] whereas rapid induction of SOX2 levels via an inducible system leads to dramatic decreases in the growth of some cells. 16,17 Therefore, we engineered BxPC3 and Capan1 cells with a stably integrated, Dox-inducible USP9X shRNA vector. More specifically, we employed a lentiviral vector that constitutively expresses the reverse tet-transactivator, as well as introduces an USP9X shRNA construct with an associated red-fluorescent protein reporter, under the control of a tetresponsive element (Fig.…”

Sox2 Acts in a Dose-Dependent Fashion to Regulate Proliferation of Cortical Progenitors

“…While this study focuses on the role of SoxB1 protein in the regulation of stem and progenitor cells in the healthy brain, it is notable that reduced Sox2 expression levels are a hallmark of gastric cancers and high levels of Sox2 have tumor suppressor functions in brain cancer cells (Cox et al, 2012). In addition, it is tempting to speculate that other Sox transcription factors may employ a similar regulatory mechanism in controlling precursor self-renewal.…”

“…Analyses conducted both in the developing and adult CNS demonstrate that SoxB1 protein function is both sufficient and a prerequisite to maintaining cells in a mitotically active precursor state (Sarkar and Hochedlinger, 2013). Despite this fact, overexpression or misexpression of SoxB1 proteins in immortalized cells in vitro has actually been shown to reduce their proliferation rate (Cox et al, 2012;Otsubo et al, 2008), while removal of one of the SoxB1 genes, Sox2, causes quiescent Muller-glia progenitors in the adult mouse retina to become mitotically active (Surzenko et al, 2013). However, the mechanisms by which differences in Sox2 expression levels can alter a cell's cell-cycle kinetics are not understood.…”