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A HIF-1α/Wnt signaling-dependent control of gene transcription regulates neuronal differentiation of glioblastoma stem cells

ABSTRACT: HIF-1α plays a crucial role in sustaining glioblastoma (GBM) cell growth and the maintenance of their undifferentiated phenotype. However, HIF-1α has been suggested to interplay with Wnt signaling components, thus activating a neuronal differentiation process in both GBM and normal brain. Here, we show that a β-catenin/TCF1/HIF-1α complex directly controls the transcription of neuronal differentiation genes in hypoxia. Conversely, at higher oxygen levels, the increased expression of TCF4 exerts a transcriptional inhibitory function on the same genomic regions, thus counteracting differentiation. Moreover, we demonstrate the existence of a positive correlation between HIF-1α, TCF1 and neuronal phenotype in GBM tumors, accompanied by the over-expression of several Wnt signaling components, finally impacting on patient prognosis. In conclusion, we unveil a mechanism by which TCF1 and HIF-1α induce a reminiscent neuronal differentiation of hypoxic GBM cells, which is hampered, in normoxia, by high levels of TCF4, thus de facto sustaining cell aggressiveness. In this study we unveil a tightly regulated mechanism by which HIF-1α controls the balance of Wnt signaling co-factors and how their molecular interplay regulates the peculiar transcriptional events responsible for the phenotypic shift of GBM stem cells toward a reminiscent neuronal differentiation, which might represent a future potential strategy to therapeutically weaken their aggressiveness.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113512 | GEO | 2019/08/21

REPOSITORIES: GEO

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Project description:Despite being subjected to high dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a Cancer Stem Cell (CSC) subpopulation, already demonstrated to better resist and evade treatments, further frustrate potential therapeutic approaches. In this context, we previously demonstrated that GBM is characterized by a tightly regulated balance between the β-catenin cofactors TCF1 and TCF4, with high levels of TCF4 responsible for sustaining CSC in these tumors, thus supporting their aggressive features. Since Histone Deacetylase Inhibitors (HDI) have been reported to strongly reduce TCF4 levels in colon cancer cells, we hypothesized they could exert a similar therapeutic action also in GBM. Here, we treated primary GBM cultures with Trichostatin-A and Vorinostat, demonstrating their ability to strongly suppress the Wnt dependent pathways, thus promoting CSC differentiation, and concomitantly impairing GBM cell viability and proliferation. More interestingly, analysis of their molecular effects suggested a prominent HDI action against GBM cell motility/migration, that we demonstrated to be dependent on the inhibition of the RhoA-GTPase and interferon intracellular cascades. Our results suggest HDI as potential therapeutic agents in GBM through their action on multiple cancer hallmarks. Glioblastoma (GBM) is considered the deadliest brain tumor, with patients displaying a high incidence of relapse and a 3-year survival of only 3-5%. For these reasons, investigation of the molecular basis of the disease could provide novel targets for therapy and improve patient prognosis. Based on our previous data demonstrating that high levels of the transcription factor TCF4 (TCF7L2) sustain the aggressiveness and the stem cell features of these tumors, in this study we tested the ability of the histone deacetylase inhibitors (HDI) Trichostatin-A and Vorinostat to suppress TCF4 levels. We demonstrated that HDI treatment impairs proliferation and viability of GBM cells. Moreover, molecular analysis of HDI effects disclosed their ability to counteract tumor cell motility by affecting the RhoA-GTPase and the interferon pathways, supporting their further characterization as potential anti-GBM agents

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A HIF-1α/Wnt signaling-dependent control of gene transcription regulates neuronal differentiation of glioblastoma stem cells

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