JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma
| Autor: | Nisitha Jayatilleke, Giorgio Milazzo, Giovanni Perini, Andrew E. Tee, Michelle Haber, Hong-Xi Xu, Yang Li, Murray D. Norris, Matthew S. Wong, Zhichao Xi, Chen C. Jiang, Stefan Hüttelmaier, Xiaoqiong Chen, Roberto Ciaccio, Pei Y. Liu, Qihan Dong, Rebecca C. Poulos, Rani E. George, Belamy B. Cheung, Chelsea Mayoh, Yuting Sun, Jessica L. Bell, Glenn M. Marshall, Xu D. Zhang, Matthias Fischer, Tao Liu, Nicholas Ho, Qing Lan, Christoph Bartenhagen, Jenny Y. Wang, Jason W. H. Wong |
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| Přispěvatelé: | 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., Norris M.D., Zhang X.D., Marshall G.M., Wang J.Y., Huttelmaier S., Fischer M., Wong J.W.H., Xu H., Perini G., Dong Q., George R.E., Liu T. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Jumonji Domain-Containing Histone Demethylases Carcinogenesis General Physics and Astronomy Apoptosis 02 engineering and technology medicine.disease_cause chemistry.chemical_compound Mice Neuroblastoma Neuroblastoma JMJD6 N-Myc E2F2 BRD4 E2F2 Transcription Factor lcsh:Science E2F2 Cancer Regulation of gene expression Mice Inbred BALB C Multidisciplinary Histone deacetylase inhibitor 021001 nanoscience & nanotechnology Gene Expression Regulation Neoplastic Female 0210 nano-technology Protein Binding medicine.drug_class Science Receptors Cell Surface Biology General Biochemistry Genetics and Molecular Biology Article Proto-Oncogene Proteins c-myc Paediatric cancer 03 medical and health sciences Panobinostat Embryonal neoplasms medicine Animals Humans neoplasms Cell Proliferation General Chemistry medicine.disease Histone Deacetylase Inhibitors 030104 developmental biology chemistry Tumor progression Cancer research lcsh:Q N-Myc |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor. |
| Databáze: | OpenAIRE |
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