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 Hüttelmaier, Matthias Fischer, Jason W. H. Wong, Hongxi Xu (), Giovanni Perini, Qihan Dong, Rani E. George and Tao Liu ()
Additional contact information
Matthew Wong: Children’s Cancer Institute Australia
Yuting Sun: Children’s Cancer Institute Australia
Zhichao Xi: Shanghai University of Traditional Chinese Medicine
Giorgio Milazzo: University of Bologna
Rebecca C. Poulos: Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Australia
Christoph Bartenhagen: University Hospital, University of Cologne
Jessica L. Bell: Martin Luther University
Chelsea Mayoh: Children’s Cancer Institute Australia
Nicholas Ho: Children’s Cancer Institute Australia
Andrew E. Tee: Children’s Cancer Institute Australia
Xiaoqiong Chen: Shanghai University of Traditional Chinese Medicine
Yang Li: Shanghai University of Traditional Chinese Medicine
Roberto Ciaccio: University of Bologna
Pei Y. Liu: Children’s Cancer Institute Australia
Chen C. Jiang: The University of Newcastle
Qing Lan: the Second Affiliated Hospital of Soochow University
Nisitha Jayatilleke: Children’s Cancer Institute Australia
Belamy B. Cheung: Children’s Cancer Institute Australia
Michelle Haber: Children’s Cancer Institute Australia
Murray D. Norris: Children’s Cancer Institute Australia
Xu D. Zhang: The University of Newcastle
Glenn M. Marshall: Children’s Cancer Institute Australia
Jenny Y. Wang: Children’s Cancer Institute Australia
Stefan Hüttelmaier: Martin Luther University
Matthias Fischer: University Hospital, University of Cologne
Jason W. H. Wong: Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Australia
Hongxi Xu: Shanghai University of Traditional Chinese Medicine
Giovanni Perini: University of Bologna
Qihan Dong: The University of Sydney
Rani E. George: Dana-Farber Cancer Institute and Boston Children’s Hospital
Tao Liu: Children’s Cancer Institute Australia

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11132-w

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