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

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.

E2F1; Endometrial cancer; Glycolysis; PKM2; TRIB3.