Protective role of epithelial deoxyhypusine synthase in colorectal carcinogenesis caused by deletion of the adenomatous polyposis coli gene

Abstract

Mutations in the adenomatous polyposis coli (APC) gene lead to the formation of adenomatous polyps in the colon that can evolve into carcinoma. We have reported that deoxyhypusine synthase (DHPS), the rate-limiting enzyme for the synthesis of the amino acid hypusine on the eukaryotic translation initiation factor 5A, plays a major role in intestinal homoeostasis. Here, we investigated the role of hypusination in sporadic colorectal cancer (CRC). GEO database analyses revealed increases in polyamine metabolism genes, including DHPS, in human CRC. Tumors exhibited increased immunostaining for DHPS compared non-tumor tissues. Then, we generated mice with tamoxifen-inducible disruption of both Apc and Dhps in intestinal epithelial cells. Compared to animals with deletion of Apc only, survival and body weight loss were worsened in mice with specific deletion of both Apc and Dhps. Moreover, these animals had increased tumor number, tumor burden, and adenomas with low-grade or high-grade dysplasia. Differential label-free quantitative proteomic analysis on colonic epithelial cells demonstrated that DHPS activity in the tumors supported the translation of enzymes implicated in detoxification of deleterious electrophiles. Thus, tumors from mice with Apc and Dhps deletion exhibited increased malondialdehyde-dilysyl crosslinks. Further, the exacerbated tumorigenesis in mice with deletion of Apc and Dhps was significantly reduced by treatment with a scavenger of electrophiles, 2-hydroxybenzylamine. Thus, epithelial hypusination is essential to dampen the initiation of adenoma formation, notably by reducing the deleterious effects of reactive aldehydes. Strategies to enhance hypusination, such as by spermidine supplementation, may have potential for chemoprevention of CRC.