TRIM39 suppresses endometrioid endometrial carcinoma progression via ubiquitination and degradation of HOXB9.

Abstract

Endometrioid endometrial carcinoma (EEC) is the major histological type of endometrial cancer, the most common gynecological malignancies in the world, and its incidence and mortality continue to increase. However, the molecular mechanism of its occurrence and development has not been fully elucidated, which limits the development of effective treatment strategies. By integrating transcriptome data from multiple public databases and validation analysis of clinical samples, we found for the first time that E3 ubiquitin ligase TRIM39 was significantly and universally down-regulated in EEC tissues. Further functional experiments in vitro and in vivo showed that restoring TRIM39 expression effectively inhibited tumor cell proliferation, colony formation ability, migration and invasion, and reversed epithelial-mesenchymal transition (EMT) process. Mechanistically, through co-immunoprecipitation and ubiquitination analysis, we revealed that TRIM39 directly binds to and mediates the K48-linked polyubiquitination of HOXB9, which promotes its proteasomal degradation. Critical rescue experiments confirmed that re-overexpression of HOXB9 partially reversed TRIM39-mediated tumor suppression. Taken together, this study not only identifies TRIM39 as an important novel tumor suppressor in EEC for the first time, but also illustrates a novel "TRIM39-HOXB9" protein stability axis, which provides new molecular insights into understanding the progression of EEC. TRIM39 was identified as a potential therapeutic target and prognostic biomarker for the disease.

Supplementary information: The online version contains supplementary material available at 10.1007/s10616-026-01033-4.