Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction

Qiuhui Yang; Ziyang Nie; Yukun Zhu; Mingying Hao; Siqi Liu; Xuelu Ding; Feng Wang; Fei Wang; Xin Geng

doi:10.1155/2023/6897268

Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction

Oxid Med Cell Longev. 2023 Apr 18:2023:6897268. doi: 10.1155/2023/6897268. eCollection 2023.

Authors

Qiuhui Yang^#^{1

2}, Ziyang Nie^#^{1

2

3}, Yukun Zhu^#^{1

2

4}, Mingying Hao^{1

2}, Siqi Liu^{1

2}, Xuelu Ding^{1

2

5}, Feng Wang⁶, Fei Wang⁷, Xin Geng^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
² Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China.
³ School of Life Sciences, Central China Normal University, Hubei Province, China.
⁴ Fuyang Hospital Affiliated to Anhui Medical University, Anhui Province 236000, China.
⁵ Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University, General Hospital, Tianjin 300052, China.
⁶ Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
⁷ Department of Neurology, General Hospital, Tianjin Medical University, Tianjin 300052, China.

^# Contributed equally.

Abstract

Background: Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown.

Objective: We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study.

Methods: Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis.

Results: By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells.

Conclusion: Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.

MeSH terms

Apoptosis / genetics
Autophagic Cell Death*
Cell Proliferation
Ferroptosis* / genetics
Telomere
Telomeric Repeat Binding Protein 2 / metabolism

Substances

Telomeric Repeat Binding Protein 2