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| Status |
Public on Sep 14, 2017 |
| Title |
Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2/M cell cycle arrest and enhanced vincristine sensitivity in Ewing sarcoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
A chimeric fusion between the RNA binding protein EWS and the ETS family transcription factor FLI1 (EWS-FLI1), created from a chromosomal translocation, is implicated in driving the majority of Ewing sarcomas (ES) by modulation of transcription and alternative splicing. The small molecule YK-4-279 inhibits EWS-FLI1 function and induces apoptosis. We tested 69 anti-cancer drugs in combination with YK-4-279 and found that vinca alkaloids exhibited synergy with YK-4-279 in five ES cell lines. The combination of YK-4-279 and vincristine reduced tumor burden and increased survival in mice bearing ES xenografts. We determined that independent drug-induced events converged to cause this synergistic therapeutic effect. YK-4-279 rapidly induced G2/M arrest, increased the abundance of cyclin B1, and decreased EWS-FLI1–mediated expression of microtubule-associated proteins, which rendered cells more susceptible to microtubule depolymerization by vincristine. YK-4-279 reduced the expression of the EWS-FLI1 target gene encoding ubiquitin ligase UBE2C, and this in part contributed to the increase in cyclin B1. Biochemical assays revealed that YK-4-279 also increased the abundance of proapoptotic isoforms of MCL1 and BCL2, presumably through inhibition of alternative splicing by EWS-FLI1, thus promoting cell death in response to vincristine. Thus a combination of vincristine and YK-4-279 might be therapeutically effective in ES patients.
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| Overall design |
Examination of mRNA profiles of TC32 on knockdown of EWS-FLI1 or treatment with YK-4-279: 3 samples Total: 1 TC32 WT Control, 1 TC32 shEF, 1 TC32 YK
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| Contributor(s) |
Zöllner SK, Selvanathan SP, Graham GT, Commins RM, Hong S, Moseley E, Parks S, Haladyna JN, Erkizan HV, Dirksen U, Hogarty MD, Üren A, Toretsky JA |
| Citation(s) |
28974650 |
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| Submission date |
Sep 13, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Garrett Thomas Graham |
| E-mail(s) |
gtg9@georgetown.edu
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| Phone |
8148822017
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| Organization name |
Georgetown University Medical Center
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| Department |
Oncology
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| Street address |
3970 Reservoir Rd NW
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| City |
Washington |
| State/province |
DC |
| ZIP/Postal code |
20007 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA407215 |
| SRA |
SRP117619 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE103837_RAW.tar |
1.9 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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