Open AccessGTSE1 promotes SNAIL1 degradation by facilitating its nuclear export in hepatocellular carcin oma cells
Author(s) -
Shanshan Li,
Dongmei Chen,
Lubiao Chen,
Huan Wei,
Jialiang Wang,
Jian Xiao,
Yanlin Huang,
Yifan Lian
Publication year - 2021
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2021.12093
Subject(s) - gene knockdown , cycloheximide , downregulation and upregulation , nuclear export signal , small interfering rna , biology , microbiology and biotechnology , epithelial–mesenchymal transition , cell cycle , subcellular localization , cancer research , smad , oncogene , cytoplasm , transcription factor , messenger rna , cell culture , transfection , cell , signal transduction , protein biosynthesis , cell nucleus , gene , biochemistry , genetics
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.