DMBX1 facilitates tumor progression via triggering epithelial-mesenchymal transition and cancer cell stemness mediated by DMBX1/PAX2/SOX5 axis in prostate cancer cells.

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with metastatic and castration-resistant disease posing significant therapeutic challenges largely driven by epithelial-mesenchymal transition (EMT) and cancer stemness (CSC). This study identifies the transcription factor DMBX1 as a potential upstream regulator of these aggressive phenotypes in vitro and in subcutaneous xenograft models. DMBX1 is significantly upregulated in PCa tissues and cell lines, and its high expression correlates with advanced disease stage and poor patient prognosis. Functional assays demonstrated that DMBX1 knockdown suppressed PCa cell proliferation, migration, invasion, and tumor growth in vivo, while its overexpression promoted these malignant behaviors. Mechanistically, RNA sequencing and subsequent analyses revealed that DMBX1 transcriptionally activates PAX2 by directly binding to its promoter. DMBX1 and PAX2 proteins physically interact and form a complex that co-occupies the promoter of the core pluripotency factor SOX5, synergistically driving its expression. This novel DMBX1/PAX2/SOX5 axis facilitates PCa progression by concurrently activating the PI3K/AKT, MAPK, and JAK/STAT3 signaling pathways, thereby altering the expression of EMT- and CSC-related markers. Collectively, our findings establish the DMBX1/PAX2/SOX5 transcriptional axis as a potential regulator associated with the control of EMT- and CSC-related markers in prostate cancer, revealing a crucial signaling hub and a promising therapeutic target for advanced PCa.