Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes

Sheng Chieh Hsu, Chia Lin Chen, Mei Ling Cheng, Cheng Ying Chu, Chun A. Changou, Yen Ling Yu, Shauh Der Yeh, Tse Chun Kuo, Cheng Chin Kuo, Chih Pin Chuu, Chien Feng Li, Lu Hai Wang, Hong Wu Chen, Yun Yen, David K. Ann, Hung Jung Wang, Hsing Jien Kung

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7527-7545
Number of pages19
JournalTheranostics
Volume11
Issue number15
DOIs
StatePublished - 2021

Keywords

  • Arginine starvation
  • cGAS-STING activation
  • DNA leakage
  • Epigenetic gene silencing

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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