TRIB3 promotes endometrial cancer progression through interacting with E2F1 and enhancing PKM2-mediated tumor glycolysis

IF 4.1 2区医学 Q1 OBSTETRICS & GYNECOLOGY

Gynecologic oncology Pub Date : 2025-09-24 DOI:10.1016/j.ygyno.2025.09.008

Feng Geng , Yanqiu Wang , Guoying Cui , Mingjun Fan

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引用次数: 0

Abstract

Aim

Our purpose was to explore the effect and the potential mechanisms of tribbles pseudokinase 3 (TRIB3) on endometrial cancer (EC).

Methods

Single-cell RNA sequencing and the Cancer Genome Atlas (TCGA) data were used for detecting TRIB3 expression in EC. The expression of TRIB3 in human EC and para-carcinoma non-tumor tissues was examined using immunohistochemistry, qRT-PCR, and western blot. The oncogenic function of TRIB3 was verified both in vitro and in vivo. The interaction among TRIB3, E2F transcription factor 1 (E2F1) and pyruvate kinase M2 (PKM2) was studied via qRT-PCR, western blot, co-immunoprecipitation, dual luciferase reporter, immunofluorescence double staining, ubiquitination assay, and chromatin immunoprecipitation.

Results

TRIB3 was upregulated in EC tissues and its high expression was correlated with poor survival of patients with EC. Gain- and loss-of-function analyses showed that TRIB3 possessed strong pro-proliferative, anti-apoptotic, pro-metastatic, and pro-glucolytic capacities in EC. TRIB3 could interact with E2F1 to inhibit its degradation. The stablely expressed E2F1 acted as a transcription factor for PKM2 to enhance its expression. Rescue experiments confirmed that TRIB3 promoted EC cell malignant behavior and glycolysis via stabilizing E2F1 and enhancing PKM2 transcription. In xenograft mouse models, TRIB3 silencing inhibited EC growth and glycolysis. In addition, indapamide was identified as a compound inhibitor of TRIB3 to supress EC growth in vitro and in vitro.

Conclusion

TRIB3 could promote the progression of EC through interacting with E2F1 and enhancing PKM2-mediated tumor glycolysis.

Abstract Image

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TRIB3通过与E2F1相互作用和增强pkm2介导的肿瘤糖酵解来促进子宫内膜癌的进展。

目的：探讨tribbles pseudokinase 3 （TRIB3）在子宫内膜癌（EC）中的作用及其潜在机制。方法：采用单细胞RNA测序和肿瘤基因组图谱（TCGA）数据检测TRIB3在EC中的表达。采用免疫组织化学、qRT-PCR和western blot检测TRIB3在人EC和癌旁非肿瘤组织中的表达。体外和体内实验均证实了TRIB3的致癌功能。通过qRT-PCR、western blot、共免疫沉淀、双荧光素酶报告基因、免疫荧光双染色、泛素化实验和染色质免疫沉淀等方法研究TRIB3、E2F转录因子1 （E2F1）和丙酮酸激酶M2 （PKM2）之间的相互作用。结果：TRIB3在EC组织中表达上调，其高表达与EC患者生存不良相关。功能增益和功能损失分析表明，TRIB3在EC中具有很强的促增殖、抗凋亡、促转移和促糖代谢能力。TRIB3可以与E2F1相互作用，抑制其降解。稳定表达的E2F1作为PKM2的转录因子，增强其表达。救援实验证实TRIB3通过稳定E2F1和增强PKM2转录促进EC细胞的恶性行为和糖酵解。在异种移植小鼠模型中，TRIB3沉默抑制EC生长和糖酵解。此外，吲达帕胺被鉴定为TRIB3的复合抑制剂，在体外和体外抑制EC生长。结论：TRIB3通过与E2F1相互作用，增强pkm2介导的肿瘤糖酵解作用，促进EC的进展。

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来源期刊

Gynecologic oncology 医学-妇产科学

CiteScore

8.60

自引率

6.40%

发文量

1062

审稿时长

37 days

期刊介绍： Gynecologic Oncology, an international journal, is devoted to the publication of clinical and investigative articles that concern tumors of the female reproductive tract. Investigations relating to the etiology, diagnosis, and treatment of female cancers, as well as research from any of the disciplines related to this field of interest, are published. Research Areas Include: • Cell and molecular biology • Chemotherapy • Cytology • Endocrinology • Epidemiology • Genetics • Gynecologic surgery • Immunology • Pathology • Radiotherapy