NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53

Abstract

A cohort of genes associated with embryonic stem (ES) cell behaviour, including NANOG, are expressed in a number of human cancers. They form an ES-like signature we first described in glioblastoma multiforme (GBM), a highly invasive and incurable brain tumour. We have also shown that HEDGEHOG-GLI (HH-GLI) signalling is required for GBM growth, stem cell expansion and the expression of this (ES)-like stemness signature. Here, we address the function of NANOG in human GBMs and its relationship with HH-GLI activity. We find that NANOG modulates gliomasphere clonogenicity, CD133 þ stem cell cell behavior and proliferation, and is regulated by HH-GLI signalling. However, GLI1 also requires NANOG activity forming a positive loop, which is negatively controlled by p53 and vice versa. NANOG is essential for GBM tumourigenicity in orthotopic xenografts and it is epistatic to HH-GLI activity. Our data establish NANOG as a novel HH-GLI mediator essential for GBMs. We propose that this function is conserved and that tumour growth and stem cell behaviour rely on the status of a functional GLI1-NANOG-p53 network.

The emerging role of p53 in stem cells

“…In this tumor type, Nanog, a homeoprotein required to maintain ES pluripotency [66], appears essential for SC functions as its inactivation reduces neurosphere formation in vitro and GBM growth in vivo. Importantly, in this system, p53 negatively regulates Nanog [65], suggesting a role for p53 in the control of both CSC selfrenewal and GBM growth.…”

“…This activity may contribute to the tumor suppressor function of p53 in brain CSCs, as recently shown in glioblastoma multiforme (GBM), a highly invasive type of brain tumor [65]. In this tumor type, Nanog, a homeoprotein required to maintain ES pluripotency [66], appears essential for SC functions as its inactivation reduces neurosphere formation in vitro and GBM growth in vivo.…”

Neuronal stem cells in the central nervous system and in human diseases

“…Some embryonic stem cell markers associated with glioma identification and aggressiveness, such as Oct4, Nanog, and Sox2, have been used for the guidance of glioma therapeutic selection (Ben-Porath et al, 2008;Holmberg et al, 2011;Shats et al, 2011). Interestingly, Nanog expression correlates with the ability of GSC formation and the malignancy of glioma clinical samples (Zbinden et al, 2010;Niu et al, 2011).…”

Expression of NANOG in human gliomas and its relationship with undifferentiated glioma cells

“…In contrast, Ben-porath et al reported that gliomas express a core es-like stem signature including nAnog (26). subsequently, Zbinden et al addressed the function of nAnog in human glioblastomas and its relationship with HH-glI activity (27). However, comprehensive and systematic studies of nAnog mrnA and protein expression in glioma cell lines in vitro and in distinct multiple glioma pathological types particularly low-grade gliomas in vivo as well as its relationship with other important glioma undifferentiation markers in situ in cellular levels are still lacking mainly considering the scarce sample data or the limitations in methodology.…”