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Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes
- Source :
- Theranostics, vol 11, iss 15, Theranostics
- Publication Year :
- 2021
- Publisher :
- eScholarship, University of California, 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Aging
Arginine
DNA Repair
Arginine starvation
Medicine (miscellaneous)
Castration-Resistant
0302 clinical medicine
2.1 Biological and endogenous factors
Aetiology
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Cancer
Prostate Cancer
Nucleotidyltransferases
Chromatin
Cell biology
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Prostatic Neoplasms, Castration-Resistant
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
PC-3 Cells
HIV/AIDS
Histone Demethylases
Development of treatments and therapeutic interventions
Research Paper
Epigenetic gene silencing
Urologic Diseases
Programmed cell death
DNA damage
DNA repair
1.1 Normal biological development and functioning
Oncology and Carcinogenesis
Biology
03 medical and health sciences
Downregulation and upregulation
Underpinning research
Genetics
Humans
Epigenetics
Gene Silencing
Nutrition
Neoplastic
Membrane Proteins
Prostatic Neoplasms
030104 developmental biology
Gene Expression Regulation
DNA leakage
cGAS-STING activation
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Theranostics, vol 11, iss 15, Theranostics
- Accession number :
- edsair.doi.dedup.....a8957a0f2b3a566773fdd63ceb1efd36