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| Status |
Public on Aug 21, 2015 |
| Title |
Activation of the Integrated Stress Response by a Jumonji Histone Demethylase Inhibitor Induces Pro-Apoptotic Metabolic Reprogramming in Multiple Myeloma |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Regulation of gene expression by chromatin modification through methylation of histone lysine residues is a dynamic, reversible process that when deregulated is associated with cancer development. In multiple myeloma, combined inhibition of the histone demethylases JARID1B, UTX and JmjD3 by the small molecule GSK-J4 prevents cellular glutamine utilization leading to amino acids deprivation, activates the integrated stress response via GCN2-dependent ATF4 activation, and induces apoptosis. This response is associated with a profound upregulation of metallothionein genes. Combined with clinical data demonstrating that overexpression of JARID1B is associated with shorter survival in multiple myeloma patients, this study highlights histone demethylases as epigenetic drug targets and places this demethylase inhibitor chemotype as having unique potential relative to established anti-myeloma treatment options.
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| Overall design |
In total there are 7 different samples analyzed and one input control. Treatments are carried out with the demethylase inhibitor (or DMSO as negative control) at 6h and 48h, or with LNA targeting demethylases (or scrambled LNA) at 7 days. A negative control at 0h is included.
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| Contributor(s) |
Pliuskys L, Hookway E, Lari F, Cain P, Pawlyn C, Reed M, Brotherton D, Davies F, Tumber A, Che K, Mazitschek R, Kucukkose C, Koca D, Gulacti F, Martinez F, Thinnes CC, Novak R, Schofield CJ, Korr D, Mund C, Wilson D, Prinjha R, Edwards CM, Gallone G, Ponting CP, Brennan PE, Bunnage M, O’Mahony A, Gronemeyer H, Günther UL, Lindow M, Ørum H, Obad S, Morgan G, Athanasou N, Christianson JC, Oppermann U |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Aug 21, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Laurynas Pliuskys |
| Organization name |
University of Oxford
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| Department |
NDORMS
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| Lab |
Professor Udo Oppermann Lab
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| Street address |
Windmill Rd
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| City |
Oxford |
| ZIP/Postal code |
OX3 7LD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA258666 |
| SRA |
SRP045686 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE60626_RAW.tar |
1.2 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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