NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disease, which may further develop into colitis-associated cancer (CAC) with the increasing morbidity. Although the mechanism of IBD is not fully understood, it9s well-recognized that adherens junction (AJ) plays an important role in gut homeostasis and pathogenesis of IBD. Our group firstly reported N-Myc downstream-regulated gene 2 (NDRG2) as a novel tumor suppressor gene. Much evidences showed that NDRG2 inhibited colorectal cancer proliferation and metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated cancer is unclear. In this study, we found that Ndrg2 deficiency aggravates colitis initiation and colitis-associated tumor development using an intestine-specific Ndrg2 knockout mouse. We proved the novel mechanism that N-terminal region of NDRG2 enhanced the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail ubiquitination and degradation. And Ndrg2 loss led to AJ structure destruction via E-cadherin reduction, resulting in diminished epithelial barrier function and enhanced gut permeability. Furthermore, in human IBD patients, NDRG2 was positively correlated with E-cadherin expression, whereas negatively correlated with inflammation degree and Snail expression. Thus, our study has revealed that NDRG2 is an essential intestinal epithelial barrier regulator and plays important roles in gut homeostasis maintenance and colitis-associated tumor development.