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| Status |
Public on Jun 28, 2021 |
| Title |
Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes [microarray] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
One of the most common metabolic defects of cancer cells is the deficiency in arginine synthesis due to suppressed expression of argininosuccinate synthetase 1 (ASS1) which renders cancer cells auxotrophic to external arginine supply. Arginine deprivation has been effectively used as a treatment for leukemias, with several clinical trials on solid tumors underway. We previously showed that in prostate cancer arginine depletion induced mitochondrial dysfunction and excessive ROS production resulting in chromatin autophagy, nuclear DNA leakage, and cellular death, but the detailed mechanism of arginine starvation-induced cell death remains unclear. In this study, we demonstrated that arginine deprivation coordinately suppressed metabolic genes, including those responsible for mitochondrial oxidative phosphorylation (OXPHOS), nucleotide metabolism, and DNA repair. The consequent ROS production and impaired DNA damage response resulted in nuclear DNA leakage and cGAS-STING activation which is accompanied by upregulation of type I interferon response. We also showed that coordinated silencing of OXPHOS and DNA repair genes is caused in part by the depletion of α-ketoglutarate (αKG) and inactivation of histone demethylases. Supplementing cell-permeable dimethyl α-ketoglutarate (DMKG) both reduced repressive histone methylations and partially restored OXPHOS gene expressions, mitochondrial functions, and mitigated nuclear DNA leakage. Using our dietary arginine-restriction model, we demonstrate that arginine starvation slows prostate cancer growth with evidence of enhanced interferon responses and recruitment of immune cells. Our data suggests arginine starvation induces cell killing of ASS1-low cancer cells by metabolic depletion and epigenetic silencing of metabolic genes, leading to DNA damage and leakage. Resulting cGAS-STING activation may further enhance these killing effects.
We used microarray to analyze the expression difference between control and arginine-depleted cells to find out what genes involved in the regulation of mitochondrial function and arginine deprivation-induced cell death.
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| Overall design |
CWR22Rv1 and PC3 cells were cultured in arginine-free medium for indicated duration. For the control group, the cells were maintained in the same arginine-free medium supplemented with arginine as the ATCC suggested. Gene expression difference was analyzed with Clariom™ S Assay, human (Affymatrix).
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| Contributor(s) |
Hsu S |
| Citation(s) |
34158865 |
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| Submission date |
Jun 03, 2020 |
| Last update date |
Jun 28, 2021 |
| Contact name |
Sheng-Chieh Hsu |
| Organization name |
National Tsing Hua University
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| Department |
Institute of Biotechnology
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| Street address |
No. 101, Section 2, Kuang-Fu Road
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| City |
Hsinchu |
| ZIP/Postal code |
30013 |
| Country |
Taiwan |
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| Platforms (1) |
| GPL23159 |
[Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay) |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE151855 |
Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes. |
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| Relations |
| BioProject |
PRJNA637045 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE151719_RAW.tar |
13.3 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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