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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 04, 2019 |
| Title |
A MYC/GCN2/eIF2alpha negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Tumours depend on altered rates of protein synthesis for growth and survival, suggesting that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools and strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2alpha via the GCN2 and PKR kinases. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, demonstrating that a negative MYC/eIF2alpha feedback loop constitutes a targetable vulnerability of colorectal tumours.
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| Overall design |
RNA-seq analysis in a human colorectal cancer cell line with doxycycline-inducible restoration of full-length APC expression. Riboseq (samples titled Riboseq_Ribo*) and corresponding RNA-seq (samples titled Riboseq_RNA*) of shEIF2B5-3 and shCTR in SW480TetOnAPC cells. To identify genes that are required for the growth of APCdef, but not of APCres cells, a drop-out screen was performed in which SW480TetOnAPC cells were infected with a lentiviral shRNA library that targets 5,000 potentially druggable genes using 27,500 shRNAs.
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| Contributor(s) |
Schmidt S, Gay D, Uthe FW, Denk S, Paauwe M, Matthes N, Diefenbacher ME, Bryson S, Warrander FC, Erhard F, Ade CP, Baluapuri A, Walz S, Jackstadt R, Ford C, Vlachogiannis G, Valeri N, Otto C, Schülein-Völk C, Maurus K, Schmitz W, Knight JP, Wolf E, Strathdee D, Schulze A, Germer C, Rosenwald A, Sansom OJ, Eilers M, Wiegering A |
| Citation(s) |
31685988, 35673898 |
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| Submission date |
Nov 14, 2017 |
| Last update date |
Jun 16, 2022 |
| Contact name |
Martin Eilers |
| Organization name |
University of Wuerzburg
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| Department |
Chair for Biochemistry and Molecular Biology
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| Lab |
Martin Eilers
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| Street address |
Am Hubland
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| City |
Wuerzburg |
| ZIP/Postal code |
97074 |
| Country |
Germany |
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| Platforms (2) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (42)
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| Relations |
| BioProject |
PRJNA418238 |
| SRA |
SRP124930 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE106858_README.txt |
437 b |
(ftp)(http) |
TXT |
| GSE106858_RNAseq_SW480_logFC.txt.gz |
925.3 Kb |
(ftp)(http) |
TXT |
| GSE106858_Reference_barcode_sequences_Decipher_HumanModule1.txt.gz |
187.2 Kb |
(ftp)(http) |
TXT |
| GSE106858_Riboseq_RNA_SW480_rep1.txt.gz |
535.4 Kb |
(ftp)(http) |
TXT |
| GSE106858_Riboseq_RNA_SW480_rep2.txt.gz |
478.3 Kb |
(ftp)(http) |
TXT |
| GSE106858_Riboseq_RNA_SW480_rep3.txt.gz |
400.0 Kb |
(ftp)(http) |
TXT |
| GSE106858_Riboseq_RPF_SW480.txt.gz |
7.3 Mb |
(ftp)(http) |
TXT |
| GSE106858_shRNAseq_counttable.txt.gz |
616.3 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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