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GTSE1 promotes SNAIL1 degradation by facilitating its nuclear export in hepatocellular carcin oma cells.

ABSTRACT: Snail family transcriptional repressor 1 (SNAIL1) is a master inducer of the epithelial‑to‑mesenchymal transition (EMT) process, contributing to tumor metastasis and recurrence. Our previous study reported that G2 and S phase‑expressed‑1 (GTSE1) served a role in regulating SNAIL1 expression in hepatocellular carcinoma (HCC). However, the underlying mechanism remains unknown. Therefore, the present study aimed to reveal the regulatory mechanism of GTSE1 on SNAIL1 expression using in vitro assays performed in HCC cell models. It was demonstrated that endogenous SNAIL1 expression was downregulated and upregulated by GTSE1 overexpression or small interfering RNA‑mediated knockdown, respectively. Via cycloheximide chase experiments, it was identified that GTSE1 overexpression increased the protein turnover of SNAIL1, while knockdown of GTSE1 reduced its degradation rate. Furthermore, it was demonstrated that GTSE1 overexpression induced the cytoplasmic expression of SNAIL1 using immunofluorescence and subcellular fractionation methods. The nuclear export inhibitor leptomycin B was able to decrease the cytoplasmic retention of SNAIL1 caused by GTSE1 overexpression. In addition, TGF‑βI treatment increased both the mRNA and protein expression levels of GTSE1, and decreased the protein expression level of SNAIL1 without affecting its mRNA transcription in Huh7 cells. It was also found that TGF‑β signaling could upregulate the transcription of GTSE1 expression by transactivating the Smad binding elements in the GTSE1 promoter. Moreover, the TGF‑βI‑induced decrease in SNAIL1 protein expression was GTSE1‑dependent in Huh7 cells. In conclusion, the current study provides a novel mechanism via which GTSE1 affects the stability of SNAIL1 by regulating its subcellular localization in HCC cells.

SUBMITTER: Li SS

PROVIDER: S-EPMC8072310 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND & AIMS:The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. METHODS:Primary enteric glial cultures were generated from the VillinCre:Men1FL/FL:Sst-/- mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom. RESULTS:Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. CONCLUSIONS:MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.

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GTSE1 promotes SNAIL1 degradation by facilitating its nuclear export in hepatocellular carcin oma cells.

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