NUDT7 Loss Promotes Kras(G12D) CRC Development

Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that Kras(G12D)-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In Kras(G12D)-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7(−/−)) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7(−/−) and Nudt7(+/+) mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7(−/−) colons. Upregulated levels of β-catenin were observed in the colons of Kras(G12D) and AOM/DSS-treated Nudt7(−/−) mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7(−/−) mice. We observed an increased level of palmitic acid in the colon of Nudt7(−/−) mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in Kras(G12D)-driven CRC development.