BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is one of 
the main contributors to the death of prostate cancer patients. To date, the 
detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial 
role of epithelial-mesenchymal transition (EMT) in cancer metastasis, we aimed 
to analyse the expression and function of Transforming growth factor-beta 
(TGF-β) signal-associated protein named Sox5 in mCRPC.
METHODS: The protein expression levels were analysed by western blot, 
immunohistochemistry and immunofluorescence. Luciferase reporter assays and 
chromatin immunoprecipitation were employed to validate the target of Sox5. The 
effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in 
vivo.
RESULTS: Here, we found that TGF-β-induced EMT was accompanied by increased Sox5 
expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced 
by TGF-β signalling. Furthermore, we demonstrated that Smad3 could bind to the 
promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind 
to Twist1 promoter and active Twist1, which initiated EMT. Importantly, 
knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal 
phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit 
prostate cancer progression in a xenograft mouse model. In clinic, patients with 
high Sox5 expression were more likely to suffer from metastases, and high Sox5 
expression also has a lower progression-free survival and cancer 
specific-survival in clinic database.
CONCLUSIONS: Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 
promotes EMT and contributes to PCa progression.