NUDT7 Loss Promotes <i>Kras^G12D </i>CRC Development

• Main Authors: Jinsoo Song, Sujeong Park, Jinjoo Oh, Deokha Kim, Ji Hyun Ryu, Won Cheol Park, In-Jeoung Baek, Xi Cheng, Xin Lu, Eun-Jung Jin
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Cancers
• Subjects: peroxisome; colorectal cancer; peroxisomal coenzyme a diphosphatase nudt7 (nudt7); palmitic acid; β-catenin
• Online Access: https://www.mdpi.com/2072-6694/12/3/576

Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that <i>Kras^G12D</i>-driven CRC tumors demonstrate dysfunctional peroxisomal b-oxidation and identified <i>Nudt7</i> (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In <i>Kras^G12D</i>-driven CRC tumors, the expression level of <i>Nudt7</i> was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into <i>Nudt7</i> knockout (<i>Nudt7^{&#8722;/&#8722;}</i>) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of <i>Nudt7</i>-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 <i>Nudt7^{&#8722;/&#8722;}</i> and <i>Nudt7^+/+</i>mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in <i>Nudt7^{&#8722;/&#8722;} </i>colons. Upregulated levels of &#946;-catenin were observed in the colons of <i>Kras^G12D </i>and AOM/DSS<i>-</i>treated <i>Nudt7^{&#8722;/&#8722;} </i>mice and downstream targets of &#946;-catenin such as<i> Myc</i>,<i> Ccdn1, </i>and<i> Nos2</i>, were also significantly increased in the colon of <i>Nudt7^{&#8722;/&#8722;} </i>mice. We observed an increased level of palmitic acid in the colon of <i>Nudt7^{&#8722;/&#8722;} </i>mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of b-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal <i>NUDT7</i> in <i>Kras^G12D</i>-driven CRC development.