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.
Highlights
Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis
Analysis of the datasets showed that the JMJD6 gene was gained in every human neuroblastoma tissue with 17q gain, and that chromosome 17q/JMJD6 gene was gained in 172 of the total of 209 (82.30%), including 21 of 26 MYCN amplified (80.77%) and 149 of 181 MYCN-non-amplified (82.32%), human neuroblastoma tissues (Fig. 1a, b)
By analyzing matched human neuroblastoma tissue array-CGH and gene expression datasets, we have confirmed that 17q21-ter/JMJD6 gene is gained in the majority of MYCN-amplified and nonamplified human neuroblastoma tissues, and that 17q segmental gain leads to higher 17q copy number and higher JMJD6 gene expression than 17q numerical gain and 17q no gain
Summary
Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. 7 Children’s Medical Research Institute Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia. The genes survivin and insulin growth factor 2 binding protein 1 within this chromosomal region have been shown to promote neuroblastoma cell survival and increase MYCN mRNA expression, respectively[3,4]. It is not clear which genes at 17q21-ter are critical for neuroblastoma tumorigenesis. As a histone arginine demethylase, JMJD6 upregulates target gene transcription by forming a protein complex with BRD4 and demethylating histone H4 at arginine 3 (H4R3) at target gene antipause enhancers, leading to RNA polymerase II (RNA Pol II) release from promoter-proximal pause regions and aberrant gene expression in glioblastoma[7,8]. As such, targeting the demethylase or hydroxylase activity of JMJD6 alone is not an ideal strategy for effective cancer therapy
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