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

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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.

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The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report.

Susan L. Cohn, Andrew D.J. Pearson, Wendy B. London … (2009)

Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors. Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively. By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.

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Modulating Hox gene functions during animal body patterning.

Joseph Pearson, Derek Lemons, William McGinnis (2005)

With their power to shape animal morphology, few genes have captured the imagination of biologists as the evolutionarily conserved members of the Hox clusters have done. Recent research has provided new insight into how Hox proteins cause morphological diversity at the organismal and evolutionary levels. Furthermore, an expanding collection of sequences that are directly regulated by Hox proteins provides information on the specificity of target-gene activation, which might allow the successful prediction of novel Hox-response genes. Finally, the recent discovery of microRNA genes within the Hox gene clusters indicates yet another level of control by Hox genes in development and evolution.

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Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study.

Katherine K Matthay, C Patrick Reynolds, Robert C. Seeger … (2009)

PURPOSE We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or to receive chemotherapy, and subsequent treatment with 13-cis-retinoic acid (cis-RA). PATIENTS AND METHODS Patients received the same induction chemotherapy, with random assignment (N = 379) to consolidation with myeloablative chemotherapy, total-body irradiation, and ABMT versus three cycles of intensive chemotherapy. Patients who completed consolidation without disease progression were randomly assigned to receive no further therapy or cis-RA for 6 months. Results The event-free survival (EFS) for patients randomly assigned to ABMT was significantly higher than those randomly assigned to chemotherapy; the 5-year EFS (mean +/- SE) was 30% +/- 4% versus 19% +/- 3%, respectively (P = .04). The 5-year EFS (42% +/- 5% v 31% +/- 5%) from the time of second random assignment was higher for cis-RA than for no further therapy, though it was not significant. Overall survival (OS) was significantly higher for each random assignment by a test of the log(-log(.)) transformation of the survival estimates at 5 years (P < .01). The 5-year OS from the second random assignment of patients who underwent both random assignments and who were assigned to ABMT/cis-RA was 59% +/- 8%; for ABMT/no cis-RA, it was 41% +/- 8% [corrected]; for continuing chemotherapy/cis-RA, it was 38% +/- 7%; and for chemotherapy/no cis-RA, it was 36% +/- 7%. Myeloablative therapy and autologous hematopoietic cell rescue result in significantly better 5-year EFS than nonmyeloablative chemo therapy; neither myeloablative therapy with [corrected] autologous hematopoietic cell rescue nor cis-RA given after consolidation therapy significantly improved OS.

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Author and article information

Contributors

Hongjuan Cui: hcui@swu.edu.cn

Han-Fei Ding:

ORCID: http://orcid.org/0000-0001-5702-3439

hding@augusta.edu

Journal

Journal ID (nlm-ta): Oncogenesis

Journal ID (iso-abbrev): Oncogenesis

Title: Oncogenesis

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2157-9024

Publication date (Electronic): 4 January 2019

Publication date PMC-release: 4 January 2019

Publication date Collection: January 2019

Volume: 8

Issue: 1

Electronic Location Identifier: 3

Affiliations

[1 ]GRID grid.263906.8, State Key Laboratory of Silkworm Genome Biology, , Southwest University, ; Chongqing, 400716 China

[2 ]ISNI 0000 0001 0033 6389, GRID grid.254148.e, Institute of Neural Regeneration and Repair and Department of Neurology, The First Hospital of Yichang, , Three Gorges University College of Medicine, ; Yichang, 443000 China

[3 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Georgia Cancer Center, , Augusta University, ; Augusta, GA 30912 USA

[4 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Biochemistry and Molecular, Medical College of Georgia, , Augusta University, ; Augusta, GA 30912 USA

[5 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Cell Biology and Anatomy, Medical College of Georgia, , Augusta University, ; Augusta, GA 30912 USA

[6 ]ISNI 0000 0004 0419 3970, GRID grid.413830.d, Charlie Norwood VA Medical Center, ; Augusta, GA 30904 USA

[7 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Pathology, Medical College of Georgia, , Augusta University, ; Augusta, GA 30912 USA

Author information

Han-Fei Ding http://orcid.org/0000-0001-5702-3439

Article

Publisher ID: 112

DOI: 10.1038/s41389-018-0112-0

PMC ID: 6328563

PubMed ID: 30631055

SO-VID: 8250097e-bfb2-4b9e-bd1f-140fa507b283

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 20 September 2018

Date revision received : 19 November 2018

Date accepted : 11 December 2018

Funding

Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);

Award ID: R01 CA190429

Award Recipient : Jane Ding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81201551

Award ID: 81201981

Award ID: 81550031

Award ID: 81672502

Award Recipient : Liqun Yang Yunhong Zha Hongjuan Cui

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ScienceOpen disciplines: Oncology & Radiotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

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

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Karger: Oncology

Most cited references 31

The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report.

Modulating Hox gene functions during animal body patterning.

Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study.

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