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NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion

ABSTRACT: NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion

PROVIDER: PRJNA1122776 | ENA |

REPOSITORIES: ENA

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NAPRT silencing in FH-deficient renal cell carcinoma confers therapeutic vulnerabilities via NAD+ depletion

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

NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion.

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.

| S-EPMC11445649 | biostudies-literature

The role of HIF in FH-associated renal neoplasia

2011-10-24 | GSE29988 | GEO

Mycoplasmoides pneumoniae FH strain:FH

Project description:Mycoplasmoides pneumoniae FH strain:FH Genome sequencing

| PRJNA182276 | ENA

The role of HIF in FH-associated renal neoplasia

Project description:Fumarate hydratase (FH) mutations predispose to renal cysts cancer. These cancers overexpress hypoxia-inducible factor-alpha (Hif-1a). We have generated a conditional Fh1 (mouse FH) knockout mice that develop renal cysts and overexpress Hif-1a. In order to identify the contribution of Hif-1a to cyst formation we have intercrossed our mice with conditional HIf-1a KO mice. We intercrossed Fh1/Hif1a mice with kidney specific cre recombinase (Ksp-Cre) and analysed kidney cyst formation. RNA was extracted from cysts from 4xFh1 KO, 4xFh1/Hif-1a KO and 4 control mice. For each comparison littermates were used and the animals were aged 15 weeks i.e. early cystic disease.

2011-10-23 | E-GEOD-29988 | biostudies-arrayexpress

Comprehensive molecular profiling of FH-deficient renal cell carcinoma identifies molecular subtypes and novel therapeutic targets

Project description:Conducting an in-depth exploration of the multi-omics landscape of Fumarate Hydratase (FH)-deficient renal cell carcinoma (RCC), the study aimed to unravel the intricate molecular mechanisms underlying this rare and aggressive form of renal cancer. Analyzing 126 patients with FH-deficient RCC, we identified distinct variant spectrum of FH gene, with truncating mutation correlated with adverse prognostic factors and a worse response to immune checkpoint blockade. The identification of three molecular subtypes with diverse clinical/genomic characteristics and varying response to systemic treatment further enriched the understanding of the heterogeneous tumor microenvironment (particularly immune-related) in FH-deficient RCC, and suggested potential therapeutic targets. These findings offer a basis for molecular stratification, shedding light on the tailored therapeutic strategies in improving treatment response of FH-deficient RCC.

2025-03-06 | GSE291073 | GEO

Mycoplasmoides pneumoniae FH strain:FH

Project description:Mycoplasma pneumoniae FH Genome Sequencing

| PRJNA73095 | ENA

Mycoplasmoides pneumoniae FH strain:FH

Project description:Mycoplasma pneumoniae FH Genome sequencing

| PRJNA46155 | ENA

Mycoplasmoides pneumoniae FH strain:FH

Project description:Mycoplasma pneumoniae FH genome sequencing project

| PRJNA49525 | ENA

Genome-wide expression profile in FH-deficient (UOK262) vs FH-competent (UOK262pFH) human cells derived from metastatsis to the mediastinum of a HLRCC patient

Project description:Comparison of the transcriptome of human kideny cancer cells either wild-type for FH or FH-deficient. The UOK262 cells were isolated from mediastinum metastasis of a HLRCC patient (Yang et al. Cancer Genetics and Cytogenetics, Volume 196, Issue 1, 1 January 2010, Pages 45–55). FH function was restored in the UOK262 by re-expressing the FH transcript from an exogenous plasmid.

2016-09-22 | GSE77538 | GEO

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