NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion
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PROVIDER: PRJNA1122776 | ENA |
REPOSITORIES: ENA
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Project description:Genome wide DNA methylation profiling of normal kidney and FH-deficient renal cell carcinoma cell lines, as well as wild type and IDH1 mutant glioma cell lines to understand patterns of DNA methylation in oncometabolite-producing cancer cell lines. The Illumina Human EPIC Bead Array (850k) platform was used to obtain methylation beta values of over 850k CpG sites throughout the genome across all cell lines.
2024-07-01 | GSE269619 | GEO
Project description:Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with the silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis, in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi). NAPRT silencing was also associated with synergistic tumor cell killing with PARP inhibitors and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite-associated hypermethylation can impact diverse cellular processes and lead to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARP inhibitors.
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Project description:Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show for the first time that the NAD biosynthetic enzyme nicotinate phosphoribosyltransferase (NAPRT), the rate-limiting enzymes in the intracellular synthesis of NAD from nicotinic acid, is physiologically present in human sera, where it acts as a novel DAMP. We detected NAPRT in plasma/sera from human donors by antibody-mediated luminex assays and mass spectrometry. Exposure of human and mouse macrophages to NAPRT triggers activation of ERK1/2, phosphorylation of IKKα/β and nuclear translocation of the p65 subunit of the NF-kB complex, with synthesis and secretion of inflammatory cytokines, including IL-1β, IL-8, TNFα and CCL3. Furthermore, NAPRT enhances monocyte differentiation into macrophages, by inducing macrophage colony-stimulating factor. These effects are independent of the NAPRT catalytic activity, but rely on the protein’s binding to TLR4, as demonstrated by showing direct in vitro interaction and by the in vivo lack of NAPRT effects in TLR4-/- macrophages. In line with the finding that NAPRT mediates endotoxin tolerance, sera from patients with sepsis or septic shock contain the highest levels of circulating NAPRT, compared to other chronic inflammatory conditions, including cancer. Importantly, patients with serum NAPRT >15 ng/ml are characterized by a worse clinical outcome, compared to the counterparts. Together, these data identify NAPRT as a novel endogenous ligand for TLR4 and a critical mediator of inflammation.
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Project description:NAPRT-mediated deamidated biosynthesis of nicotinamide adenine dinucleotide (NAD), an essential electron carrier for hundreds of biochemical reactions in all living cells, mediates the diet-microbe-host NAD metabolic interaction in mice. To study the function of this metabolic pathway in vivo, we recently generated a mutant mouse strain (NAPRT KO) in which a 21-nt fragment that encodes 7 amino acids in the catalytic domain of NAPRT was deleted in all cells using the CRISPR/Cas9-mediated gene editing technology. Our results showed that NAPRT is highly expressed in the gut epithelial cells, where it functions to maintain the cellular NAD pool for an efficient response to stress-induced acute NAD depletion. Consistently, NAPRT deficiency impairs DNA repair, sensitizes mice to AOM-induced gut DNA damage. Here we profiled transcriptomic changes in the colon of WT and NAPRT KO mice at different time points after injection of AOM.
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Project description:NAPRT-mediated deamidated biosynthesis of nicotinamide adenine dinucleotide (NAD), an essential electron carrier for hundreds of biochemical reactions in all living cells, mediates the diet-microbe-host NAD metabolic interaction in mice. To study the function of this metabolic pathway in vivo, we recently generated a mutant mouse strain (NAPRT KO) in which a 21-nt fragment that encodes 7 amino acids in the catalytic domain of NAPRT was deleted in all cells using the CRISPR/Cas9-mediated gene editing technology. Our data showed that NAPRT KO mice are hypersensitive to DSS-induced colitis. To better understand this hypersensitivity at the molecular level, we analyzed transcriptomes of colon tissues from DSS-treated WT and NAPRT KO mice.
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Project description:NAPRT-mediated deamidated biosynthesis of nicotinamide adenine dinucleotide (NAD), an essential electron carrier for hundreds of biochemical reactions in all living cells, mediates the diet-microbe-host NAD metabolic interaction in mice. To study the function of this metabolic pathway in vivo, we recently generated a mutant mouse strain (NAPRT KO) in which a 21-nt fragment that encodes 7 amino acids in the catalytic domain of NAPRT was deleted in all cells using the CRISPR/Cas9-mediated gene editing technology. Our data showed that NAPRT KO mice are hypersensitive to DSS-induced colitis. To better understand this hypersensitivity at the molecular level, we analyzed transcriptomes of colon tissues from DSS-treated WT and NAPRT KO mice.
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Project description:NAD biosynthetic enzymes are widely considered oncogenic due to their frequent overexpression in cancer to support elevated metabolic demand. This dataset is in support of a manuscript where we identify a tumor-suppressive role for the deamidated NAD biosynthesis pathway in both mice and humans. Unlike the ubiquitously expressed amidated salvage enzyme, NAPRT the first enzyme of the deamidated pathway is selectively enriched in gut epithelial cells, where it sustains NAD levels during stress-induced acute depletion. Loss of NAPRT compromises PARP activity and DNA repair, increasing susceptibility to chemically induced colitis, tumorigenesis, and age-associated spontaneous tumors in mice. Consistently, low NAPRT expression correlates with poor prognosis across multiple human cancers. These findings demonstrate that endogenous deamidated NAD biosynthesis suppresses tumorigenesis, and that enhancing this pathway may offer a strategy for tumor prevention.
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