Transcriptional Repression of p53 by PAX3 Contributes to Gliomagenesis and Differentiation of Glioma Stem Cells.

Hui Zhu,Yibing Guo,Xiaohong Li,Qianqian Liu,Chengbin Xue,Qianqian Han,Hongkui Wang,Qingfeng Huang,Jingjing Lu

doi:10.3389/fnmol.2018.00187

Abstract

Although there are available therapies as surgery, chemotherapy and radiation, glioblastoma (GBM) still has been considered as the most common and overwhelming primary tumor of brain. In GBM, the brain glioma stem cells (BGSCs) were identified and played a crucial role in resistance of GBM to conventional therapies described above. PAX3 was previously identified by our group as a diagnostic/prognostic marker and a therapeutic regulator in the therapy of GBM. Here, we hypothesized PAX3/p53 axis promoted the process of differentiation, regulating to the cancer stem cell properties, such as proliferation and migration. The correlation between PAX3 and p53 in GBM were first clarified. Immunofluorescence of p53 was shown activated following BGSCs differentiation. We further identified that PAX3 might specifically bind to the promoter of p53 gene, and transcriptionally repressed p53 expression. ChIP assay further confirmed that PAX3/p53 axis regulated the differentiation process of BGSCs. Then, the function of PAX3 in BGSCs were sequentially investigated in vitro and in vivo. Ectopic PAX3 expression promoted BGSCs growth and migration while PAX3 knockdown suppressed BGSCs growth, migration in vitro and in vivo. Similar to PAX3 overexpression, p53 inhibition also showed increase in growth and migration of differentiated BGSCs. Regarding the functional interaction between PAX3 and p53, PAX3 knockdown-mediated decrease in proliferation was partially rescued by p53 inhibition. Hypoxia significantly promoted the migration potential of BGSCs. In addition, hypoxia inducible factor-1α (HIF-1α) might be a potential upstream regulator of PAX3 in differentiated BGSCs under hypoxia. Our work may provide a supplementary mechanism in regulation of the BGSCs differentiation and their functions, which should provide novel therapeutic targets for GBM in future.

Highlights

Brain tumors are generally classified according to pathological features
Considering that PAX3 expression was inversely correlated with p53 expression during brain glioma stem cells (BGSCs) differentiation, we examined the role of PAX3 in regulating p53 expression
We further identified that PAX3 might bind to the promoter of p53 gene, and transcriptionally repressed p53 expression

Summary

Introduction

Brain tumors are generally classified according to pathological features. Among them, non-malignant corresponds to Grade I and II tumors, and malignant corresponds to Grade III and IV tumors, while glioblastoma (GBM) corresponds to Grade IV tumors (Louis et al, 2016). The recurrence of GBM has been well known to be resistant to radiation and chemotherapy that caused by brain glioma stem cells (BGSCs; Beier et al, 2011). Discovered in GBM, BGSCs likely play crucial roles in resistance of tumors to conventional therapies and vascular formation of glioma (Liebelt et al, 2016). Besides microenvironmental factors, these features present potential targets for precisely targeting therapy against the BGSCs in GBM (Liebelt et al, 2016). It has been increasingly acknowledged that another way to target BGSCs is to alter the ability of BGSCs to interact with their microenvironment

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Conclusion