MTA1 aggravates experimental colitis in mice by promoting transcription factor HIF1A and up-regulating AQP4 expression

Abstract

AbstractExperimental colitis can persist as a chronic disease, accompanied with an underlying risk of development into colorectal cancer. Metastasis-associated protein 1 (MTA1), as a chromatin modifier, exerts notable association with multiple diseases, including colitis. The current study aims to investigate the mechanism of MTA1/HIF1A/AQP4 axis in experimental colitis in mice. First, experimental colitis mouse models were established using dextran sulfate sodium (DSS) and in vitro colonic epithelial cells FHC inflammation models were with lipopolysaccharide (LPS) for determination of MTA1 and HIF1A expressions. It was found that MTA1 and HIF1A were both highly-expressed in experimental colitis samples. Results of dual-luciferase reporter gene assay and ChIP assay further revealed that MTA1 activated HIF1A, and subsequently induced AQP4 transcription to up-regulate AQP4 in experimental colitis. Following loss- and gain-function, the effects of MTA1/HIF1A/AQP4 axis on apoptosis and viability of colon epithelial cells were detected by a combination of TUNEL staining and flow cytometry, and CCK-8 assay. It was observed that silencing of MAT1 in the FHC and NCM460 cells reduced IL-1β and TNF-α expressions induced by LPS. Meanwhile, AQP4 promoted LPS-induced inflammation, and exacerbated apoptosis of colon epithelial cells and augmented experimental colitis development in mice. In vivo experiments further verified that TGN-020 treatment effectively alleviated DSS-induced experimental colitis in mice and diminished apoptosis of colon epithelial cells. Altogether, MTA1 may promote AQP4 transcription by activating HIF1A, thus exacerbating DSS-induced experimental colitis in mice, which provides a novel direction for the treatment of experimental colitis.