JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Matthew Wong; Yuting Sun; Zhichao Xi; Giorgio Milazzo; Rebecca C. Poulos; Christoph Bartenhagen; Jessica L. Bell; Chelsea Mayoh; Nicholas Ho; Andrew E. Tee; Xiaoqiong Chen; Yang Li; Roberto Ciaccio; Pei Y. Liu; Chen C. Jiang; Qing Lan; Nisitha Jayatilleke; Belamy B. Cheung; Michelle Haber; Murray D. Norris; Xu D. Zhang; Glenn M. Marshall; Jenny Y. Wang; Stefan Huttelmaier; Matthias Fischer; Jason W. H. Wong; Hongxi Xu; Giovanni Perini; Qihan Dong; Rani E. George; Tao Liu

doi:10.1038/s41467-019-11132-w

JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Matthew Wong, Yuting Sun, Zhichao Xi, Giorgio Milazzo, Rebecca C. Poulos, Christoph Bartenhagen, Jessica L. Bell, Chelsea Mayoh, Nicholas Ho, Andrew E. Tee, Xiaoqiong Chen, Yang Li, Roberto Ciaccio, Pei Y. Liu, Chen C. Jiang, Qing Lan, Nisitha Jayatilleke, Belamy B. Cheung, Michelle Haber, Murray D. NorrisXu D. Zhang, Glenn M. Marshall, Jenny Y. Wang, Stefan Huttelmaier, Matthias Fischer, Jason W. H. Wong, Hongxi Xu, Giovanni Perini, Qihan Dong, Rani E. George, Tao Liu

Western Sydney University

Research output: Contribution to journal › Article › peer-review

Abstract

Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.

Original language	English
Article number	3319
Number of pages	15
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-11132-w
Publication status	Published - 2019

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Keywords

carcinogenesis
genes
neuroblastoma
pediatrics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-11132-w

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Wong, M., Sun, Y., Xi, Z., Milazzo, G., Poulos, R. C., Bartenhagen, C., Bell, J. L., Mayoh, C., Ho, N., Tee, A. E., Chen, X., Li, Y., Ciaccio, R., Liu, P. Y., Jiang, C. C., Lan, Q., Jayatilleke, N., Cheung, B. B., Haber, M., ... Liu, T. (2019). JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nature Communications, 10, Article 3319. https://doi.org/10.1038/s41467-019-11132-w

@article{ab70e74ba23f44439a2f7102063fbbe6,

title = "JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma",

abstract = "Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.",

keywords = "carcinogenesis, genes, neuroblastoma, pediatrics",

author = "Matthew Wong and Yuting Sun and Zhichao Xi and Giorgio Milazzo and Poulos, {Rebecca C.} and Christoph Bartenhagen and Bell, {Jessica L.} and Chelsea Mayoh and Nicholas Ho and Tee, {Andrew E.} and Xiaoqiong Chen and Yang Li and Roberto Ciaccio and Liu, {Pei Y.} and Jiang, {Chen C.} and Qing Lan and Nisitha Jayatilleke and Cheung, {Belamy B.} and Michelle Haber and Norris, {Murray D.} and Zhang, {Xu D.} and Marshall, {Glenn M.} and Wang, {Jenny Y.} and Stefan Huttelmaier and Matthias Fischer and Wong, {Jason W. H.} and Hongxi Xu and Giovanni Perini and Qihan Dong and George, {Rani E.} and Tao Liu",

year = "2019",

doi = "10.1038/s41467-019-11132-w",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Wong, M, Sun, Y, Xi, Z, Milazzo, G, Poulos, RC, Bartenhagen, C, Bell, JL, Mayoh, C, Ho, N, Tee, AE, Chen, X, Li, Y, Ciaccio, R, Liu, PY, Jiang, CC, Lan, Q, Jayatilleke, N, Cheung, BB, Haber, M, Norris, MD, Zhang, XD, Marshall, GM, Wang, JY, Huttelmaier, S, Fischer, M, Wong, JWH, Xu, H, Perini, G, Dong, Q, George, RE & Liu, T 2019, 'JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma', Nature Communications, vol. 10, 3319. https://doi.org/10.1038/s41467-019-11132-w

TY - JOUR

T1 - JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

AU - Wong, Matthew

AU - Sun, Yuting

AU - Xi, Zhichao

AU - Milazzo, Giorgio

AU - Poulos, Rebecca C.

AU - Bartenhagen, Christoph

AU - Bell, Jessica L.

AU - Mayoh, Chelsea

AU - Ho, Nicholas

AU - Tee, Andrew E.

AU - Chen, Xiaoqiong

AU - Li, Yang

AU - Ciaccio, Roberto

AU - Liu, Pei Y.

AU - Jiang, Chen C.

AU - Lan, Qing

AU - Jayatilleke, Nisitha

AU - Cheung, Belamy B.

AU - Haber, Michelle

AU - Norris, Murray D.

AU - Zhang, Xu D.

AU - Marshall, Glenn M.

AU - Wang, Jenny Y.

AU - Huttelmaier, Stefan

AU - Fischer, Matthias

AU - Wong, Jason W. H.

AU - Xu, Hongxi

AU - Perini, Giovanni

AU - Dong, Qihan

AU - George, Rani E.

AU - Liu, Tao

PY - 2019

Y1 - 2019

N2 - Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.

AB - Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.

KW - carcinogenesis

KW - genes

KW - neuroblastoma

KW - pediatrics

UR - http://hdl.handle.net/1959.7/uws:52539

U2 - 10.1038/s41467-019-11132-w

DO - 10.1038/s41467-019-11132-w

M3 - Article

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 3319

ER -

JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Abstract

Open Access - Access Right Statement

Keywords

UN SDGs

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