SOX4-Mediated Post-Transcriptional suppression of PTEN via miR-106b~25 Cluster Contributes to Prostate Cancer Aggressiveness.

Abstract

Molecular based risk stratification of prostate cancer (PCa) holds significant potential for guiding precision therapeutic strategies. Previous studies revealed SOX4 activation drives PCa progression in PTEN deficient tumors through the PI3K-AKT signaling pathway. However, the mechanistic interplay between SOX4 and PTEN, as well as their clinical utility for prognostic stratification, remains to be elucidated. In this study, we revealed that SOX4 expression is increased in PCa patients with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in PCa patients. Importantly, PCa patients exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive PCa subtype associated with unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput microRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses PCa cell proliferation, migration and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b~25/PTEN pathway model in promoting PCa progression and propose a potential therapeutic strategy for this high-risk subtype. Implications: SOX4 suppresses PTEN through the transcriptional upregulation of miR-106b~25, rendering tumors sensitive to combined inhibition of SOX4 and PI3K-AKT in prostate cancer.