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; Tao Liu

doi:10.1038/s41467-019-11132-w

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.

Authors

Matthew Wong¹, Yuting Sun¹, Zhichao Xi^{2

3

4}, Giorgio Milazzo⁵, Rebecca C Poulos^{6

7}, Christoph Bartenhagen⁸, Jessica L Bell⁹, Chelsea Mayoh¹, Nicholas Ho¹, Andrew E Tee¹, Xiaoqiong Chen^{2

4}, Yang Li^{2

4}, Roberto Ciaccio⁵, Pei Y Liu¹, Chen C Jiang¹⁰, Qing Lan¹¹, Nisitha Jayatilleke¹, Belamy B Cheung¹, Michelle Haber¹, Murray D Norris^{1

12}, Xu D Zhang¹⁰, Glenn M Marshall^{1

13}, Jenny Y Wang¹, Stefan Hüttelmaier⁹, Matthias Fischer⁸, Jason W H Wong^{6

14}, Hongxi Xu^{15

16}, Giovanni Perini⁵, Qihan Dong^{3

17}, Rani E George^{18

19}, Tao Liu²⁰

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. [email protected].
¹⁶ Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
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. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Carcinogenesis
Cell Proliferation / drug effects
E2F2 Transcription Factor / genetics
E2F2 Transcription Factor / metabolism
Female
Gene Expression Regulation, Neoplastic
Histone Deacetylase Inhibitors / administration & dosage
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
Jumonji Domain-Containing Histone Demethylases / genetics
Jumonji Domain-Containing Histone Demethylases / metabolism*
Male
Mice
Mice, Inbred BALB C
Neuroblastoma / drug therapy*
Neuroblastoma / genetics
Neuroblastoma / metabolism
Neuroblastoma / physiopathology
Protein Binding
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Receptors, Cell Surface / antagonists & inhibitors
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*

Substances

E2F2 Transcription Factor
Histone Deacetylase Inhibitors
Proto-Oncogene Proteins c-myc
Ptdsr protein, mouse
Receptors, Cell Surface
JMJD6 protein, human
Jumonji Domain-Containing Histone Demethylases

Grants and funding

R01 CA197336/CA/NCI NIH HHS/United States