Wnt-Induced Stabilization of KDM4C Is Required for Wnt/β-Catenin Target Gene Expression and Glioblastoma Tumorigenesis

Abstract Wnt/β-catenin signaling activates the transcription of target genes to regulate stem cells and cancer development. However, the contribution of epigenetic regulation to this process is unknown. Here, we report that Wnt activation stabilizes the epigenetic regulator KDM4C that promotes tumorigenesis and survival of human glioblastoma cells by epigenetically activating the transcription of Wnt target genes. KDM4C protein expression was upregulated in human glioblastomas, and its expression directly correlated with Wnt activity and Wnt target gene expression. KDM4C was essential for Wnt-induced gene expression and tumorigenesis of glioblastoma cells. In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation. Wnt3a stabilized KDM4C through inhibition of GSK3-dependent protein kinase R activity. Stabilized KDM4C accumulated in the nucleus and bound to and demethylated TCF4-associated histone H3K9 by interacting with β-catenin, promoting HP1γ removal and transcriptional activation. These findings reveal that Wnt–KDM4C–β-catenin signaling represents a novel mechanism for the transcription of Wnt target genes and regulation of tumorigenesis, with important clinical implications. Significance: These findings identify the Wnt–KDM4C–β-catenin signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.