Title |
Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma
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Published in |
Science Translational Medicine, May 2018
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DOI | 10.1126/scitranslmed.aao4680 |
Pubmed ID | |
Authors |
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber |
Abstract |
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. In addition, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Furthermore, GSK-J4 and RA combination increased differentiation and ER stress over GSK-J4 effects and limited the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, PUMA induction by GSK-J4 sensitized tumors to the B cell lymphoma 2 (BCL-2) inhibitor venetoclax, demonstrating that epigenetic-targeted therapies and BCL-2 homology domain 3 mimetics can be rationally combined to treat this high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust antineuroblastoma activity. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 3 | 18% |
United Kingdom | 2 | 12% |
Canada | 1 | 6% |
Brazil | 1 | 6% |
India | 1 | 6% |
Unknown | 9 | 53% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 12 | 71% |
Scientists | 3 | 18% |
Science communicators (journalists, bloggers, editors) | 2 | 12% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 92 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 20 | 22% |
Student > Ph. D. Student | 12 | 13% |
Other | 7 | 8% |
Student > Master | 7 | 8% |
Student > Doctoral Student | 4 | 4% |
Other | 12 | 13% |
Unknown | 30 | 33% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 22 | 24% |
Agricultural and Biological Sciences | 10 | 11% |
Medicine and Dentistry | 8 | 9% |
Immunology and Microbiology | 6 | 7% |
Chemistry | 3 | 3% |
Other | 9 | 10% |
Unknown | 34 | 37% |