Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151855 | GEO | 2021/06/28
REPOSITORIES: GEO
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Project description: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.
| S-EPMC8210599 | biostudies-literature
Project description: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.
2021-06-28 | GSE151719 | GEO
Project description: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.
2021-06-28 | GSE151809 | GEO
Project description:Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes.
| PRJNA637495 | ENA
Project description:Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes [microarray]
| PRJNA637045 | ENA
Project description:Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes [ChIP-seq]
| PRJNA637313 | ENA
Project description:Limited effective targets have challenged the treatment of oral squamous cell carcinoma (OSCC). Casein kinase 2 interacting protein 1 (CKIP-1) is a scaffold protein involved in various diseases. However, the role of CKIP-1 in OSCC remains unclear. The aim of this study was to explore the regulatory role of CKIP-1 in OSCC, as well as the involved mechanism. First, higher expression of CKIP-1 in OSCC tissues and cell lines were found. Series of gain- and loss-of-function experiments demonstrated suppressed malignant behaviours and enhanced apoptosis of OSCC cells when CKIP-1 was silenced. Also, inhibited tumour growth in CKIP-1-silenced group were proved. Further, mitochondrial transcription factor A (TFAM) downregulation, increased ROS production, decreased mitochondrial membrane potential and cGAS-STING activation in CKIP-1-silenced group were observed. The involvement of mitochondrial homeostasis-related TFAM/cGAS-STING axis in CKIP-1-silenced OSCC cells was finally demonstrated by tetramethylpyrazine (TMP) that inhibits TFAM degradation. Taken together, our study demonstrated that CKIP-1 silencing could significantly antagonize OSCC via TFAM/cGAS-STING axis, which may provide a candidate target for OSCC treatment.
| S-EPMC11338841 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.
| S-EPMC10232002 | biostudies-literature
Project description:Novel approaches are needed to boost the efficacy of immune checkpoint blockade (ICB) therapy. Ataxia telangiectasia mutated (ATM) protein plays a central role in sensing DNA double-stranded breaks (DSBs) and coordinating their repair. Recent data indicated that ATM might be a promising target to enhance ICB therapy. However, the molecular mechanism involved has not been clearly elucidated. Here, we show that ATM inhibition could potentiate ICB therapy by promoting cytoplasmic leakage of mitochondrial DNA (mtDNA) and activation of the cGAS/STING pathway. We show that genetic depletion of ATM in murine cancer cells delayed tumor growth in syngeneic mouse hosts in a T cell-dependent manner. Furthermore, chemical inhibition of ATM potentiated anti-PD-1 therapy of mouse tumors. ATM inhibition potently activated the cGAS/STING pathway and enhanced lymphocyte infiltration into the tumor microenvironment by downregulating mitochondrial transcription factor A (TFAM), which led to mtDNA leakage into the cytoplasm. Moreover, our analysis of data from a large patient cohort indicated that ATM mutations, especially nonsense mutations, predicted for clinical benefits of ICB therapy. Our study therefore provides strong evidence that ATM may serve as both a therapeutic target and a biomarker to enable ICB therapy.
| S-EPMC7843232 | biostudies-literature
Project description:BackgroundAs one of the most common malignancy, lung adenocarcinoma (LUAD) is characterized by low 5-year survival rate. This research aimed to investigate the effects of ribonucleotide reductase regulatory subunit M2 (RRM2) on malignant biological behaviors and activation of cGAS/STING pathway. We also explored the synergistic sensitization mechanisms of RRM2 and radiotherapy.MethodsBioinformatic tools were used to evaluate the clinical significance of RRM2 in LUAD patients. The roles of RRM2 in malignant phenotype and DNA damage in LUAD cells were investigated with cell proliferation, colony formation, immunofluorescence, modified Boyden chamber and comet assays. The mouse models were used to evaluate the biological significance of RRM2 in vivo. Cytotoxic T cell infiltration was evaluated via flow cytometric analysis and immunohistochemistry staining in C57BL/6 mice. We also explored the synergistic effects of RRM2 silencing and radiation on LUAD cells with apoptosis assay and immunoblotting in vitro.ResultsBioinformatic analysis revealed that RRM2 had diagnostic values for LUAD patients. Higher levels of RRM2 predicted worse prognosis. RRM2 silencing inhibited LUAD cell proliferation, invasion and migration. RRM2 knockdown induced S phase arrest and DNA damage. RRM2 silencing induced cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, and the downstream targets were regulated in a STING-dependent manner. Knockdown of RRM2 suppressed tumor growth in the xenograft tumor models. RRM2 deficiency increased CD8 + T cells in the tumor tissues and spleens. Furthermore, RRM2 silencing had synergistic effects with radiation on inhibiting cell proliferation and promoting apoptosis. Meanwhile, this combination promoted the activation of cGAS/STING signaling pathway synergistically, and simultaneously increased expression of IFNβ, CCL5 and CXCL10.ConclusionOur results demonstrated that RRM2 silencing had anti-tumor values and activated the cGAS/STING signaling pathway. RRM2 silencing increased CD8 + T cells infiltration. RRM2 silencing cooperated with radiation to inhibit LUAD cell proliferation, promote apoptosis and enhance the activation of cGAS/STING signaling pathway. RRM2 could be a promising target for tumor regression through cancer immunotherapy in LUAD.
| S-EPMC8051110 | biostudies-literature