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Series GSE150244 Query DataSets for GSE150244
Status Public on Jun 30, 2021
Title RNA-seq profiling of Ewing sarcoma cells after TRIM8 knockout and EWS/FLI over-expression
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif- containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared to >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion-oncoprotein specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF driven cancers.
 
Overall design TC71 Ewing sarcoma cells engineered to express FKBP12F36V-HA-TRIM8 was treated with either DMSO control or dTAGV-1 for 24 hours to induce TRIM8 degradation. In addition, TC71 Ewing sarcoma cells engineered to express doxycycline-inducible EWS/FLI-HA was treated with either water control or doxycycline (500ng/mL) for 8 hours. Triplicates for all groups were used for paired-end RNA-sequencing.
 
Contributor(s) Seong BA, Dharia NV, Lin S, Donovan KA, Chong S, Robichaud A, Conway A, Hamze A, Ross L, Alexe G, Adane B, Nabet B, Ferguson F, Stolte B, Wang EJ, Sun J, Darzacq X, Piccioni F, Gray NS, Fischer ES, Stegmaier K
Citation(s) 34329586
Submission date May 11, 2020
Last update date Sep 29, 2021
Contact name Neekesh V. Dharia
E-mail(s) neekeshdharia@gmail.com
Organization name Dana-Farber Cancer Institute
Department Pediatric Oncology
Lab Kimberly Stegmaier
Street address 350 Brookline Ave
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (12)
GSM4543966 TC71_dT_T8_DMSO_24h_Rep1
GSM4543967 TC71_dT_T8_DMSO_24h_Rep2
GSM4543968 TC71_dT_T8_DMSO_24h_Rep3
Relations
BioProject PRJNA631627
SRA SRP261076

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE150244_TRIM8_BN_DM_24h_DESeq2_DESeq2_LFC_apeglm.txt.gz 607.0 Kb (ftp)(http) TXT
GSE150244_TRIM8_BN_DM_24h_DESeq2_log2p1_tpm_data.txt.gz 688.2 Kb (ftp)(http) TXT
GSE150244_TRIM8_iEFdox_DESeq2_DESeq2_LFC_apeglm.txt.gz 857.0 Kb (ftp)(http) TXT
GSE150244_TRIM8_iEFdox_DESeq2_log2p1_tpm_data.txt.gz 954.0 Kb (ftp)(http) TXT
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Processed data are available on Series record

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