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 holds significant potential for guiding precision therapeutic strategies. Previous studies revealed that SOX4 activation drives prostate cancer 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 patients with prostate cancer with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in patients with prostate cancer. Importantly, patients with prostate cancer exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive prostate cancer subtype associated with an unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput miRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of the miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads to hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses prostate cancer cell proliferation, migration, and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b∼25/PTEN pathway model in promoting prostate cancer 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.