JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Nat Commun. 2019 Jul 25;10(1):3319. doi: 10.1038/s41467-019-11132-w.

Matthew Wong ¹, Yuting Sun ¹, Zhichao Xi ² ³ ⁴, Giorgio Milazzo ⁵, Rebecca C Poulos ⁶ ⁷, Christoph Bartenhagen ⁸, Jessica L Bell ⁹, Chelsea Mayoh ¹, Nicholas Ho ¹, Andrew E Tee ¹, Xiaoqiong Chen ² ⁴, Yang Li ² ⁴, Roberto Ciaccio ⁵, Pei Y Liu ¹, Chen C Jiang ¹⁰, Qing Lan ¹¹, Nisitha Jayatilleke ¹, Belamy B Cheung ¹, Michelle Haber ¹, Murray D Norris ¹ ¹², Xu D Zhang ¹⁰, Glenn M Marshall ¹ ¹³, Jenny Y Wang ¹, Stefan Hüttelmaier ⁹, Matthias Fischer ⁸, Jason W H Wong ⁶ ¹⁴, Hongxi Xu ¹⁵ ¹⁶, Giovanni Perini ⁵, Qihan Dong ³ ¹⁷, Rani E George ¹⁸ ¹⁹, Tao Liu ²⁰

Affiliations

1 Children's Cancer Institute Australia, Randwick Sydney, NSW, 2031, Australia.
2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
3 Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
4 Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
5 Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
6 Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, 2052, Australia.
7 Children's Medical Research Institute Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, 2145, Australia.
8 Department of Experimental Pediatric Oncology, University Hospital, University of Cologne, 50931, Cologne, Germany.
9 Institute of Molecular Medicine, Martin Luther University, Kurt-Mothes-Str.3a, 06120, Halle Saale, Germany.
10 School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, NSW, 2308, Australia.
11 Department of Neurosurgery, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.
12 Centre for Childhood Cancer Research, UNSW Medicine, UNSW Sydney, Kensington, Sydney, NSW, 2052, Australia.
13 Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, 2031, Australia.
14 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, 999077, China.
15 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. xuhongxi88@gmail.com.
16 Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. xuhongxi88@gmail.com.
17 School of Science and Health, The University of Western Sydney, Sydney, NSW, 2751, Australia.
18 Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, 02215, USA.
19 Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
20 Children's Cancer Institute Australia, Randwick Sydney, NSW, 2031, Australia. tliu@ccia.unsw.edu.au.

PMID: 31346162 DOI: 10.1038/s41467-019-11132-w

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-80013

THZ1

99.84%, CDK7 Inhibitor

CDK

Cancer

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