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BMC Cancer
Published in: BMC Cancer 1/2022

Open Access 01-12-2022 | Endometrial Cancer | Research

GPX4 suppresses ferroptosis to promote malignant progression of endometrial carcinoma via transcriptional activation by ELK1

Authors: Sitian Wei, Zhicheng Yu, Rui Shi, Lanfen An, Qi Zhang, Qian Zhang, Tangansu Zhang, Jun Zhang, Hongbo Wang

Published in: BMC Cancer | Issue 1/2022

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Abstract

Background

Glutathione Peroxidase 4 (GPX4) is a key protein that inhibits ferroptosis. However, its biological regulation and mechanism in endometrial cancer (EC) have not been reported in detail.

Methods

The expression of GPX4 in EC tissues was determined by TCGA databases, qRT-PCR, Western blot, and immunohistochemistry (IHC). The effects of GPX4 on EC cell proliferation, migration, apoptosis, and tumorigenesis were studied in vivo and in vitro. In addition, ETS Transcription Factor ELK1 (ELK1) was identified by bioinformatics methods, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP). Pearson correlation analysis was used to evaluate the association between ELK1 and GPX4 expression.

Results

The expression of GPX4 was significantly up-regulated in EC tissues and cell lines. Silencing GPX4 significantly inhibited the proliferation, migration ability, induced apoptosis, and arrested the cell cycle of Ishikawa and KLE cells. Knockdown of GPX4 accumulated intracellular ferrous iron and ROS, disrupted MMP, and increased MDA levels. The xenograft tumor model also showed that GPX4 knockdown markedly reduced tumor growth in mice. Mechanically, ELK1 could bind to the promoter of GPX4 to promote its transcription. In addition, the expression of ELK1 in EC was positively correlated with GPX4. Rescue experiments confirmed that GPX4 knockdown could reverse the strengthens of cell proliferation and migration ability and the lower level of Fe2+ and MDA caused by upregulating ELK1.

Conclusion

The results of the present study suggest that ELK1 / GPX4 axis plays an important role in the progress of EC by promoting the malignant biological behavior and inducing ferroptosis of EC cells, which provides evidence for investigating the potential therapeutic strategies of endometrial cancer.
Appendix
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Metadata
Title
GPX4 suppresses ferroptosis to promote malignant progression of endometrial carcinoma via transcriptional activation by ELK1
Authors
Sitian Wei
Zhicheng Yu
Rui Shi
Lanfen An
Qi Zhang
Qian Zhang
Tangansu Zhang
Jun Zhang
Hongbo Wang
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2022
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-022-09986-3

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