Abstract
BackgroundOverexpression of eukaryotic translation initiation factor 3H (EIF3H) predicts cancer progression and poor prognosis, but the mechanism underlying EIF3H as an oncogene remains unclear in esophageal squamous cell carcinoma (ESCC).MethodsTCGA database and the immunohistochemistry (IHC) staining of ESCC samples were used and determined the upregulation of EIF3H in ESCC. CCK8 assay, colony formation assay and transwell assay were performed to examine the ability of cell proliferation and mobility in KYSE150 and KYSE510 cell lines with EIF3H overexpression or knockdown. Xenograft and tail-vein lung metastatic mouse models of KYSE150 cells with or without EIF3H knockdown were also used to confirm the function of EIF3H on tumor growth and metastasis in vivo. A potential substrate of EIF3H was screened by co-immunoprecipitation assay (co-IP) combined with mass spectrometry in HEK293T cells. Their interaction and co-localization were confirmed using reciprocal co-IP and immunofluorescence staining assay. The function of EIF3H on Snail ubiquitination and stability was demonstrated by the cycloheximide (CHX) pulse-chase assay and ubiquitination assay. The correlation of EIF3H and Snail in clinical ESCC samples was verified by IHC.ResultsWe found that EIF3H is significantly upregulated in esophageal cancer and ectopic expression of EIF3H in ESCC cell lines promotes cell proliferation, colony formation, migration and invasion. Conversely, genetic inhibition of EIF3H represses ESCC tumor growth and metastasis in vitro and in vivo. Moreover, we identified EIF3H as a novel deubiquitinating enzyme of Snail. We demonstrated that EIF3H interacts with and stabilizes Snail through deubiquitination. Therefore, EIF3H could promote Snail-mediated EMT process in ESCC. In clinical ESCC samples, there is also a positive correlation between EIF3H and Snail expression.ConclusionsOur study reveals a critical EIF3H-Snail signaling axis in tumor aggressiveness in ESCC and provides EIF3H as a promising biomarker for ESCC treatment.
Highlights
Overexpression of eukaryotic translation initiation factor 3H (EIF3H) predicts cancer progression and poor prognosis, but the mechanism underlying EIF3H as an oncogene remains unclear in esophageal squamous cell carcinoma (ESCC)
EIF3H is overexpressed in ESCC We first analyzed the expression of EIF3H in esophageal cancer of TCGA data in UALCAN [42] (n = 195)
We found that EIF3H expression was much higher in the ESCC tissues compared with adjacent normal esophageal epithelial tissues (Fig. 1c and d)
Summary
Overexpression of eukaryotic translation initiation factor 3H (EIF3H) predicts cancer progression and poor prognosis, but the mechanism underlying EIF3H as an oncogene remains unclear in esophageal squamous cell carcinoma (ESCC). The eukaryotic translation initiation factor 3 (EIF3) is one of the largest complexes in mammalian cells. It contains 13 putative subunits named from EIF3A to EIF3M [8]. The METTL3-EIF3H interface is required for enhanced translation and oncogenic transformation [18]. These observations indicate that EIF3H might have great contribution to establishing and maintaining the aggressive state of cancer. We demonstrated Snail, as the novel identified substrate of EIF3H, could be deubiquitinated and stabilized by EIF3H
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