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.

中文翻译：

---

Wnt /β-连环蛋白靶基因表达和成胶质细胞瘤肿瘤发生需要Wnt诱导的KDM4C稳定化。

Wnt /β-catenin信号传导激活靶基因的转录，以调节干细胞和癌症的发展。但是，表观遗传调控对该过程的贡献尚不清楚。在这里，我们报道Wnt激活通过表观遗传激活Wnt靶基因的转录来稳定表观遗传调节剂KDM4C，后者可促进人类胶质母细胞瘤细胞的肿瘤发生和存活。在人胶质母细胞瘤中，KDM4C蛋白表达上调，其表达与Wnt活性和Wnt靶基因表达直接相关。KDM4C对于Wnt诱导的胶质母细胞瘤细胞基因表达和肿瘤发生至关重要。在没有Wnt3a的情况下，蛋白激酶R在Ser918处磷酸化KDM4C，诱导KDM4C泛素化和降解。Wnt3a通过抑制GSK3依赖性蛋白激酶R活性来稳定KDM4C。稳定的KDM4C积聚在细胞核中，通过与β-连环蛋白相互作用，促进HP1γ的去除和转录激活，与TCF4相关的组蛋白H3K9结合并脱甲基。这些发现表明，Wnt-KDM4C-β-catenin信号传导代表Wnt靶基因转录和肿瘤发生调控的新机制，具有重要的临床意义。意义：这些发现确定了Wnt-KDM4C-β-catenin信号转导轴是胶质瘤肿瘤发生的关键机制，可作为胶质母细胞瘤的新治疗靶标。这些发现表明，Wnt-KDM4C-β-catenin信号传导代表Wnt靶基因转录和肿瘤发生调控的新机制，具有重要的临床意义。意义：这些发现确定了Wnt-KDM4C-β-catenin信号转导轴是胶质瘤肿瘤发生的关键机制，可作为胶质母细胞瘤的新治疗靶标。这些发现表明，Wnt-KDM4C-β-catenin信号传导代表Wnt靶基因转录和肿瘤发生调控的新机制，具有重要的临床意义。意义：这些发现确定了Wnt-KDM4C-β-catenin信号转导轴是胶质瘤肿瘤发生的关键机制，可作为胶质母细胞瘤的新治疗靶标。