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Loss of UXS1 Selectively Depletes Pyrimidines and Induces Replication Stress in KEAP1-Mutant Lung Cancer [RNA-seq]

ABSTRACT: Kelch-like ECH associated protein 1 (KEAP1) is the third most commonly mutated gene in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. Here, we investigated synthetic lethal interaction genes in KEAP1-mutated cancer cells and identified a dependency on UDP xylose synthase 1 (UXS1), which converts UDP-glucuronic acid (UDP-GlcA) to UDP- xylose in the proteoglycan synthetic pathway. UDP glucose dehydrogenase (UGDH), a transcriptional target of NRF2 that converts UDP-glucose to UDP-GlcA, was highly expressed in KEAP1-mutant tumors. Upon UXS1 knockdown, depletion of UDP-xylose occurred in both KEAP1-mutant and wildtype (WT) cells, whereas UDP-GlcA accumulated to a greater extent in the KEAP1-mutant setting. The resulting shortage of available UDP and other pyrimidines slowed S-phase progression and stalled DNA replication fork marks, causing cells to undergo prolonged cell-cycle exit or apoptosis. Dependency on UXS1 was rescued by knocking out UGDH to prevent UDP-GlcA accumulation and UDP depletion. DNA replication stress in UXS1-depleted cells sensitized them to clinical cell-cycle checkpoint inhibitors. Further, CRISPR screening experiments identified genes that modulate UXS1 dependency. While liver had the highest normal tissue expression of UGDH, UXS1 knockout in the liver did not result in hepatotoxicity. Taken together, these data demonstrate that UXS1 is a selective dependency in KEAP1-mutant tumors and loss of UXS1 creates additional therapeutically exploitable vulnerabilities in KEAP1-mutant tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305124 | GEO | 2025/08/20

REPOSITORIES: GEO

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Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.

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Loss of UXS1 Selectively Depletes Pyrimidines and Induces Replication Stress in KEAP1-Mutant Lung Cancer [RNA-seq]

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