Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer

Abstract

Human gastric epithelium has a unique mucin gene expression pattern, which becomes markedly altered in gastrointestinal disorder. This alteration in mucin expression, including the mucin MUC5AC, may be related to the development and prognosis of gastric cancers, and MUC5AC-positive gastric cancer has been reported to be poor prognosis. However, the molecular mechanism of MUC5AC transcriptional regulation has not been fully elucidated. AT motif-binding factor 1 (ATBF1) is a homeotic transcriptional regulatory factor recently identified as a tumor suppressor gene, and its subcellular localization suggests a link to cell proliferation and differentiation. We investigated the mechanism of MUC5AC transcriptional regulation by ATBF1. In 123 gastric cancer lesions, ATBF1 expressed in the nucleus significantly suppressed MUC5AC expression, as determined by immunohistochemistry. In addition, analysis of the MUC5AC promoter region revealed an AT motif-like element. This element was found to be essential for ATBF1 suppression of MUC5AC promoter activity as shown in a dual luciferase-reporter assay. Over-expressed ATBF1 also significantly suppressed endogenous MUC5AC protein expression in gastric cancer cells. Chromatin immunoprecipitation demonstrated that ATBF1 binds to the AT motif-like element in the MUC5AC promoter. These results indicate that ATBF1 in the nucleus negatively regulates the MUC5AC gene in gastric cancer by binding to an AT motif-like element in the MUC5AC promoter. ' 2007 Wiley-Liss, Inc.

Gli Regulates MUC5AC Transcription in Human Gastrointestinal Cells

“…Sp1 and Gli are reported to enhance MUC5AC expression in human lung-epithelial and pancreatic cancer cells, respectively [24], [25]. Contrastively, ATBF1 is negatively regulate MUC5AC expression in human gastric cancer cells [26], In spite of these results, molecular mechanisms of MUC5AC expression in human gastrointestinal cells have not been fully elucidated. In the present study, we identified 15 bp sequence in human MUC5AC 5′-flanking region which plays an important role in MUC5AC expression in gastrointestinal cancer cells, and also found that the region contains a putative Gli-binding site which does not coincide with previous report [25].…”

Expression and subcellular localization of AT motif binding factor 1 in colon tumours

“…In a previous study investigating the subcellular localization of ATBF1 in gastric cancer, ATBF1 was demonstrated to bind to the AT motif in the promoter region of the mucin 5AC gene and negatively regulate its transcription (8). In addition, ATBF1 was observed to translocate to the nucleus by forming a complex with runt domain transcription factor 3 (RUNX3), in response to transforming growth factor (TGF)-β signal transduction (9).…”

Adalimumab Treatment in Biologically Naïve Crohn’s Disease: Relationship with Ectopic MUC5AC Expression and Endoscopic Improvement

“…Prunetin [27] and wogonin [28] are associated with the inhibition of MUC5AC mucin by the inhibition of the NF- κ B signaling pathway. In the stomach cancers and atrophic gastritis with Helicobacter pylori infection, it has been reported that SOX2 as a SRY-related HMG box protein and AT motif-binding factor 1 (ATBF-1) are associated with the regulation of MUC5AC expression [29–31]. Further studies also may be needed to clarify the regulation of MUC5AC expression by TNF- α , the above-mentioned factors, or other ones.…”