Transcription factor CUX1 is required for intestinal epithelial wound healing and targets the VAV2-RAC1 Signalling complex

Abstract

Intestinal epithelial cells form a protective barrier in limiting gut luminal content potentially harmful to the host. Upon gut epithelium injury, several signals instruct epithelial cells to undergo a rapid healing process. Defects in this process induce inflammatory responses and can further evolve into chronic gut inflammatory diseases. We previously identified the transcription factor CUX1 as crucial for protecting against experimental colitis in mice. However, the precise molecular mechanisms by which CUX1 intervenes during this biological process are unknown. Our aim was to evaluate CUX1 biological and functional roles during intestinal epithelial cell wound healing. RNAi knockdown of CUX1 in intestinal epithelial cells revealed a crucial role for this regulator in migratory response following wounding assays. Gene expression profiling identified several gene transcripts modulated in absence of CUX1 during wound healing for which a significant number was associated with cell motility and cytoskeleton function. Chromatin immunoprecipitation assays identified the guanine nucleotide exchange factor Vav2 gene as a direct target for CUX1. Coincidently, reduction of VAV2 in absence of CUX1 was associated with a significant decrease of RAC1 activity in response to epithelial wounding. Our results identify a novel pathway by which CUX1 regulates normal intestinal epithelial cell restitution.

THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

“…Upregulation of CUX1 stimulated proliferation, tumor growth, resistance to apoptosis and angiogenesis in Pnet (8). In the present study, CUX1 functioned as a transactivator for MMP9 transcription and induced the proliferation of pNET cells (potentially through modulating the transcription of certain effectors, for example p21, FGF1, VAV2), which was consistent with previous studies (44)(45)(46).…”

A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease

“…MiR-31-3p knockout mice display more severe intestinal inflammation as a response to chemically induced colitis (DSS), and this response can be dampened by administration of miR-31-3p [ 37 ]. Other target transcripts that play a role in intestinal epithelial maintenance are RXRA (targeted by the upregulated 155-5p, miR-1260b, miR-132-3p, miR-425-5p, miR-18a-3p, and miR-425-5p; has a key role in retinol signaling in the differentiation of mature enterocytes [ 38 ]), VAV2 (targeted by 155-5p, miR-15a/b-5p, and miR-17-5p; has a role in wound repair in the intestine and in differentiation and migration of mature enterocytes along the crypt-villous axis via RAC1 [ 39 , 40 ]), CUX1 (miR-132-3p; transcription factor targeting VAV2 [ 40 ]), and PACSIN2 (miR-155-5p, miR-1260b, miR-138-5p, and miR-361-3p; controls morphology of the microvilli [ 41 ]).…”