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| Status |
Public on Mar 23, 2020 |
| Title |
α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer [RRBS] |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how the low glutamine metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
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| Overall design |
6 samples are analyzed for RRBS sequencing ( 3 biological replicates for control samples and 3 biological replicates for DM-aKG treated samples)
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| |
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| Contributor(s) |
Kong M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Nov 12, 2019 |
| Last update date |
Mar 23, 2020 |
| Contact name |
Haiqing Li |
| E-mail(s) |
hali@coh.org
|
| Phone |
626-256-4673
|
| Organization name |
Beckman Research Institute of City of Hope, Center for Informatics
|
| Department |
Department of Computational & Quantitative Medicine
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| Lab |
Research Informatics
|
| Street address |
1500 East Duarte Road
|
| City |
Duarte |
| State/province |
CA |
| ZIP/Postal code |
91010 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE140270 |
α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer |
|
| Relations |
| BioProject |
PRJNA589067 |
| SRA |
SRP229614 |
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