Pan-cancer analysis and validation show GTF2E2's diagnostic, prognostic, and immunological roles in regulating ferroptosis in endometrial cancer.

BACKGROUND: Transcription initiation factor IIE subunit beta (GTF2E2) is a crucial component of the RNA polymerase II transcription initiation complex. There is a lack of more detailed research on the biological function of GTF2E2 in pan-cancer. METHODS: We conducted a comprehensive pan-cancer analysis using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) project. Employing a multi-pronged approach with tools including R, Cytoscape, TISIDB, cBioPortal, STRING, GSCALite, and CancerSEA, we investigated GTF2E2's expression patterns, prognostic value, mutational landscape, functional enrichment, and immunological associations across 33 cancer types. Besides, we further validated the bioinformatic results through in vitro experiments in Uterine corpus endometrial carcinoma (UCEC), including western blotting (WB), cell proliferation assays and transwell. DCFH-DA, C11-BODIPY 581/591 and FeRhoNox-1 probes were performed to identify ferroptosis levels in vitro. RESULTS: GTF2E2 expression was significantly elevated in most cancers compared to normal tissues, with notable diagnostic potential (AUC > 0.7) in 20 cancer types. GTF2E2 expression varied across molecular and immune subtypes and correlated with tumor stage and patient age in several cancers. Functional enrichment analyses highlighted GTF2E2's involvement in key cancer-related and immunological pathways. Notably, GTF2E2 promoted UCEC progression in vitro, and knockdown of GTF2E2 significantly inhibited the proliferation, migration and invasion of UCEC cells. Compared with the control group, GPX4 expression was down-regulated and ACSL4 expression was up-regulated in the GTF2E2-knockdown group. Knockdown of GTF2E2 also increased the intracellular levels of Fe2+, lipid peroxides (LPOs) and reactive oxygen species (ROS). CONCLUSIONS: Our findings underscore GTF2E2's multifaceted roles in cancer biology, highlighting its potential as a diagnostic biomarker, prognostic indicator, and immunotherapeutic target across various malignancies. This investigation has the potential to contribute significantly to a deeper understanding of the substantial involvement of GTF2E2 in human malignancies, particularly UCEC.