Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes
© The author(s)..
Rationale: One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods: Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results: We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of α-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo, with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions: Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Theranostics - 11(2021), 15 vom: 13., Seite 7527-7545 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hsu, Sheng-Chieh [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.07.2021 Date Revised 28.07.2021 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.7150/thno.54695 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM327061995 |
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| 100 | 1 | |a Hsu, Sheng-Chieh |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 28.07.2021 | ||
| 500 | |a Date Revised 28.07.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The author(s). | ||
| 520 | |a Rationale: One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods: Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results: We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of α-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo, with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions: Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Arginine starvation | |
| 650 | 4 | |a DNA leakage | |
| 650 | 4 | |a Epigenetic gene silencing | |
| 650 | 4 | |a cGAS-STING activation | |
| 650 | 7 | |a Chromatin |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Neoplasm Proteins |2 NLM | |
| 650 | 7 | |a STING1 protein, human |2 NLM | |
| 650 | 7 | |a Arginine |2 NLM | |
| 650 | 7 | |a 94ZLA3W45F |2 NLM | |
| 650 | 7 | |a Nucleotidyltransferases |2 NLM | |
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| 650 | 7 | |a cGAS protein, human |2 NLM | |
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| 700 | 1 | |a Chen, Chia-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Mei-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Cheng-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Changou, Chun A |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Yen-Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Yeh, Shauh-Der |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Tse-Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Kuo, Cheng-Chin |e verfasserin |4 aut | |
| 700 | 1 | |a Chuu, Chih-Pin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chien-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lu-Hai |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Hong-Wu |e verfasserin |4 aut | |
| 700 | 1 | |a Yen, Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Ann, David K |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hung-Jung |e verfasserin |4 aut | |
| 700 | 1 | |a Kung, Hsing-Jien |e verfasserin |4 aut | |
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