Abstract
Induction of differentiation is a therapeutic strategy in high-risk neuroblastoma, a childhood cancer of the sympathetic nervous system. Neuroblastoma differentiation requires transcriptional upregulation of neuronal genes. How this process is regulated at epigenetic levels is not well understood. Here we report that the histone H3 lysine 27 demethylase KDM6B is an epigenetic activator of neuroblastoma cell differentiation. KDM6B mRNA expression is downregulated in poorly differentiated high-risk neuroblastomas and upregulated in differentiated tumors, and high KDM6B expression is prognostic for better survival in neuroblastoma patients. In neuroblastoma cell lines, KDM6B depletion promotes cell proliferation, whereas KDM6B overexpression induces neuronal differentiation and inhibits cell proliferation and tumorgenicity. Mechanistically, KDM6B epigenetically activates the transcription of neuronal genes by removing the repressive chromatin marker histone H3 lysine 27 trimethylation. In addition, we show that KDM6B functions downstream of the retinoic acid-HOXC9 axis in inducing neuroblastoma cell differentiation: KDM6B expression is upregulated by retinoic acid via HOXC9, and KDM6B is required for HOXC9-induced neuroblastoma cell differentiation. Finally, we present evidence that KDM6B interacts with HOXC9 to target neuronal genes for epigenetic activation. These findings identify a KDM6B-dependent epigenetic mechanism in the control of neuroblastoma cell differentiation, providing a rationale for reducing histone H3 lysine 27 trimethylation as a strategy for enhancing differentiation-based therapy in high-risk neuroblastoma.
Highlights
Neuroblastoma is a common pediatric cancer of the sympathetic nervous system derived from the neural crest cell[1,2,3,4]
Kdm6b expression was selectively downregulated in sphere-forming cells compared to primary tumor cells, as no significant changes were observed in the expression levels of other demethylase genes examined (Fig. 1a)
We found that lower KDM6B expression is significantly associated with reduced event-free survival of neuroblastoma patients (Fig. 1d), with high-risk neuroblastoma tumors (Fig. 1e, left panel), and with advanced tumor stages (Fig. 1e, right panel)
Summary
Neuroblastoma is a common pediatric cancer of the sympathetic nervous system derived from the neural crest cell[1,2,3,4]. Highrisk neuroblastomas are predominantly Schwannian better understanding of the molecular basis of neuroblastoma differentiation may suggest new therapeutic targets or strategies for enhancing the efficacy of differentiation-based therapy for high-risk neuroblastoma patients. Studies of normal stem cell differentiation have demonstrated a pivotal role of epigenetic regulation via histone lysine methylation in the differentiation process[15,16]. Trimethylation of histone H3 at lysine 27 (H3K27me3) is required for the transcriptional repression of development genes and the maintenance of. Since histone lysine methylation levels are determined by the balance between the activities of histone lysine methyltransferases and demethylases[22,23], we reasoned that histone lysine demethylases (KDMs) that antagonize the activity of EZH2 by removing H3K27me[3] might have an onco-suppressor function in neuroblastoma. Our investigation provides evidence in support of this model, revealing an anti-tumorigenic activity of KDM6B in neuroblastoma cells by inducing neuronal differentiation
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