Hypoxia-inducible factor 1α (HIF-1α)-activated Gli1 induces invasion and EMT by H3K4 methylation in glioma cells

Abstract

Abstract Objectives Gliomas are highly aggressive neuroepithelial-layer malignancies. Hypoxia-inducible factor 1α (HIF-1α) was revealed to be upregulated in gliomas under hypoxia. Nevertheless, its role in glioma cells remains elusive. We attempted to clarify the molecular mechanism of HIF-1 underlying glioma. Methods Cellular models were established to mimic the characteristics of hypoxia. RT‒qPCR was used to detect HIF-1α and Gli1 levels in glioma cells with or without hypoxic treatment. Transwell assays were used to measure the invasive ability of U87 and U251 cells. Western blotting was used to evaluate epithelial-mesenchymal transition (EMT)-associated protein abundance and H3K4 methylation (H3K4me)-associated protein abundance in U87 and U251 cells. ChIP assessed the association of HIF-1α or H3K4me with the Gli1 promoter in glioma cells. Results HIF-1α and Gli1 were upregulated in glioma cells relative to normal human astrocytes (NHAs). HIF-1α and Gli1 were also upregulated in hypoxia-treated glioma cells relative to untreated glioma cells. Both HIF-1α and Gli1 silencing suppressed glioma invasion and EMT under hypoxia. HIF-1α upregulated Gli1 transcriptionally via MLL1-mediated H3K4me. H3K4me mutation silencing was further demonstrated to suppress glioma cell invasion and EMT under hypoxia. Conclusions Both HIF-1α and Gli1 are upregulated in glioma cells and function as oncogenes in glioma cells. HIF-1α transcriptionally activates Gli1 via MLL1-mediated H3K4 methylation in glioma cells, providing ideas for seeking new therapeutic directions for glioma.