Protein stabilization of ITF2 by NF-κB prevents colitis-associated cancer development

NF-kappa B activation contributes to colitis-associated colorectal cancer (CAC). Here the authors show that NF-kappa B subunit, p65 stabilizes ITF2, which then suppresses NF-kappa B downstream genes and inhibits CAC progression. Chronic colonic inflammation is a feature of cancer and is strongly associated with tumorigenesis, but its underlying molecular mechanisms remain poorly understood. Inflammatory conditions increased ITF2 and p65 expression both ex vivo and in vivo, and ITF2 and p65 showed positive correlations. p65 overexpression stabilized ITF2 protein levels by interfering with the binding of Parkin to ITF2. More specifically, the C-terminus of p65 binds to the N-terminus of ITF2 and inhibits ubiquitination, thereby promoting ITF2 stabilization. Parkin acts as a E3 ubiquitin ligase for ITF2 ubiquitination. Intestinal epithelial-specific deletion of ITF2 facilitated nuclear translocation of p65 and thus increased colitis-associated cancer tumorigenesis, which was mediated by Azoxymethane/Dextran sulfate sodium or dextran sulfate sodium. Upregulated ITF2 expression was lost in carcinoma tissues of colitis-associated cancer patients, whereas p65 expression much more increased in both dysplastic and carcinoma regions. Therefore, these findings indicate a critical role for ITF2 in the repression of colitis-associated cancer progression and ITF2 would be an attractive target against inflammatory diseases including colitis-associated cancer.

Automated summary

NF-kappa B activation contributes to the development of colitis-associated colorectal cancer. The authors found that the NF-kappa B subunit p65 stabilizes ITF2, which suppresses NF-kappa B downstream genes and inhibits cancer progression. Increased expression of ITF2 and p65 was observed under inflammatory conditions, and they showed a positive correlation. p65 overexpression stabilizes ITF2 protein levels by interfering with the binding of Parkin to ITF2. Intestinal epithelial-specific deletion of ITF2 led to increased tumorigenesis of colitis-associated cancer. Lost ITF2 expression in carcinoma tissues and increased p65 expression in dysplastic and carcinoma regions were observed in colitis-associated cancer patients. These findings suggest that ITF2 plays a critical role in repressing colitis-associated cancer progression and could be a potential target for inflammatory diseases, including colitis-associated cancer.