TY - JOUR
T1 - Histone demethylase KDM6B has an anti-tumorigenic function in neuroblastoma by promoting differentiation
AU - Yang, Liqun
AU - Zha, Yunhong
AU - Ding, Jane
AU - Ye, Bingwei
AU - Liu, Mengling
AU - Yan, Chunhong
AU - Dong, Zheng
AU - Cui, Hongjuan
AU - Ding, Han Fei
N1 - Funding Information:
We thank Rogier Versteeg and the Department of Oncogenomics at the Academic Medical Center (Amsterdam, The Netherlands) for providing the R2 Genomics Analysis and Visualization Platform. During this study, L.Y. was supported in part by the National Natural Science Foundation of China (NNSFC) grants 31672496 and 81201551, Y.Z. by the NNSFC grants 81201981 and 81550031, H.C. by the NNSFC grant 81672502 and a grant from the National Key Research and Development Program of China (2016YFC1302204), and H.-F.D. by the DoD grant W81XWH-12-1-0613 and the NIH grant R01 CA190429.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059886073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059886073&partnerID=8YFLogxK
U2 - 10.1038/s41389-018-0112-0
DO - 10.1038/s41389-018-0112-0
M3 - Article
AN - SCOPUS:85059886073
SN - 2157-9024
VL - 8
JO - Oncogenesis
JF - Oncogenesis
IS - 1
M1 - 3
ER -
