Histone demethylase KDM6B has an anti-tumorigenic function in neuroblastoma by promoting differentiation

Liqun Yang, Yunhong Zha, Jane Ding, Bingwei Ye, Mengling Liu, Chunhong Yan, Zheng Dong, Hongjuan Cui, Hanfei Ding

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3
JournalOncogenesis
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2019

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Histone Demethylases
Neuroblastoma
Epigenomics
Cell Differentiation
Histones
Lysine
Tretinoin
Cell Proliferation
Sympathetic Nervous System
Transcriptional Activation
Genes
Chromatin
Neoplasms
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Histone demethylase KDM6B has an anti-tumorigenic function in neuroblastoma by promoting differentiation. / Yang, Liqun; Zha, Yunhong; Ding, Jane; Ye, Bingwei; Liu, Mengling; Yan, Chunhong; Dong, Zheng; Cui, Hongjuan; Ding, Hanfei.

In: Oncogenesis, Vol. 8, No. 1, 3, 01.01.2019.

Research output: Contribution to journalArticle

Yang, Liqun ; Zha, Yunhong ; Ding, Jane ; Ye, Bingwei ; Liu, Mengling ; Yan, Chunhong ; Dong, Zheng ; Cui, Hongjuan ; Ding, Hanfei. / Histone demethylase KDM6B has an anti-tumorigenic function in neuroblastoma by promoting differentiation. In: Oncogenesis. 2019 ; Vol. 8, No. 1.
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