UXS1 regulates UDP-GlcA levels to support growth of UGDH-high cancer cells

Identifying genes that are crucial for cancer cell survival but dispensable in normal cells holds immense therapeutic potential. The DepMap Consortiums extensive datasets have paved the way for uncovering such selectively essential genes in cancer. However, it remained challenging to efficiently prioritize understudied, selectively essential genes for validation and characterization. To this end, our lab has previously ranked and prioritized potentially understudied, selectively essential genes based on their PubMed publication numbers. This approach led to successful identification and detailed characterization of two top understudied genes. Building on this methodology, our current research identified UXS1, an enzyme responsible for catalyzing the conversion from UDP-glucuronic acid (UDP-GlcA) to UDP-xylose, as a selectively essential gene in cancer cells expressing elevated levels of UGDH, an enzyme responsible for producing UDP-GlcA. Through an integrated approach combining genetic and biochemical assays, we discovered that UXS1 plays a critical role in these UGDH-overexpressing cancer cells by preventing the harmful buildup of UDP-GlcA, which otherwise would lead to cellular toxicity. Our findings not only validate our strategy for prioritizing underexplored but potentially pivotal selectively essential genes but also highlight UXS1 as a potential vulnerability and therapeutic target in cancers characterized by high UGDH expression.