NUDT7 Loss Promotes KrasG12D CRC Development

Abstract

Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-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 KrasG12D 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 KrasG12D-driven CRC development.

Expression and Potential Biomarkers of Regulators for M7G RNA Modification in Gliomas

“…NUDT7 and NUDT11 are both hydrolases that belong to the peroxisomal nudix family of enzymes ( 40 , 41 ). Mutations of NUDT7 have been described in colorectal cancer, inhibition of Nudt7 may contribute to the progression of Kras G12D colorectal cancer through upregulation of Wnt/β-catenin signaling and palmitic acid accumulation ( 42 ). Genetic and functional analyses showed that when NUDT11 was inhibited, colony formation of tumor-associated cell phenotypes was significantly reduced and their proliferation/survival capacity was compromised ( 43 ).…”

Role of the NUDT Enzymes in Breast Cancer

“…In 2015 the gene expression analysis of 30 cancer cell lines identified NUDT4 as a potential target [ 61 ]. The combination and analysis of muti-omic data revealed NUDT7 as having a role in colorectal and breast cancer development [ 62 , 63 ].…”

NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet

“…Indeed, NUDT7 has been identified as a candidate susceptibility gene for familial CRC, with an early truncation, p.Y37X, found in two patients ( 109 ). Additionally, Nudt7 -/- mice treated with a combination of azoxymethane and dextran sulfate sodium develop more polyps and adenocarcinoma than WT mice ( 51 ). The changes in bile acid composition that stimulate the development of CRC have recently been linked to their effect on FXR activity ( 107 ), and deletion of Nudt7 affected FXR activity in a diet- and gender-specific manner ( Fig.…”

“…Nudt7 -/- mice have been recently generated ( 50 , 51 ). These mice exhibit compromised cartilage integrity and the propensity to develop more colonic polyps, but the effect of Nudt7 deletion on (acyl-)CoA levels and global hepatic metabolism has yet to be characterized.…”