NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

Abstract

Paracellular barriers play an important role in the pathogenesis of IBDs and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumor suppressor gene and inhibits colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear. Here, We found that intestine-specific Ndrg2 deficiency caused mild spontaneous colitis with ageing, aggravated DSS and TNBS induced colitis, increased AOM-DSS induced colitis-associated tumor. Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhancing the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination, and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation. These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays important role in gut homeostasis maintenance and colitis-associated tumor development. SUMMARYAdherens junctoin (AJ) as the key part of intestinal epithelial barrier plays important role in the pathogenesis of IBDs. Intestinal specific Ndrg2 loss attenuates E-cadherin expression and disrupts the integrity of AJ structure which is feasible for colitis and tumor development.