TMEFF2 promotes hyperplastic prostate progression by degrading BAX via TRIM17

Benign prostatic hyperplasia (BPH) is a prevalent pathological condition and a significant, though not exclusive, contributor to lower urinary tract symptoms (LUTS) in aging males. Despite decades of intensive research, the molecular mechanisms underlying BPH remain elusive. We investigated the potential functional roles of TMEFF2 and its underlying mechanisms in prostatic hyperplasia.

Human hyperplastic prostate samples, cultured human prostatic cell lines and testosterone-induced rat BPH model were employed. Hematoxylin and Eosin, immunohistochemical and immunofluorescence staining, cell transfections, CCK-8 assay, flow cytometry, Transwell assay, wound healing assay, qRT-PCR, immunoprecipitation and Western blotting, cycloheximide chase assay and protein ubiquitination assay were performed.

Transcriptome analysis and subsequent experimental validation revealed TMEFF2 has emerged as a key regulator of BPH, exhibiting elevated expression levels and a positive correlation with prostate volume. Functionally, TMEFF2 depletion inhibited cell proliferation, induced cell apoptosis, and suppressed migration by preventing BAX protein degradation, thereby halting BPH progression both in vitro and in vivo. Mechanistically, TMEFF2 interacts with BAX and facilitates K48-linked ubiquitination via recruitment of the E3 ubiquitin ligase TRIM17, leading to the proteasomal degradation of BAX.

These findings clarify the function of the TMEFF2-BAX axis in BPH and underscore the therapeutic potential of TMEFF2 as a therapeutic target in BPH treatment.