Use of miR­145 and testicular nuclear receptor 4 inhibition to reduce chemoresistance to docetaxel in prostate cancer.

ABSTRACT

The human testicular nuclear receptor 4 (TR4) is a critical regulatory gene for the progression of prostate cancer (PCa). Although it has been revealed that TR4 causes chemoresistance in PCa via the activation of octamer­binding transcription factor 4 (OCT4), the detailed mechanism remains unexplored. In the present study, it was revealed that inhibition of TR4 by shRNA in PCa enhanced the sensitivity to docetaxel in vitro and in vivo. TR4 induced the downregulation of miR­145 by directly binding it to the promoter of miR­145, which was confirmed by chromatin immunoprecipitation analysis and luciferase assay. The overexpression of miR­145 suppressed both the chemoresistance and the expression of OCT4 mRNA and protein. Additionally, the TR4 shRNA mediated re­sensitization to docetaxel, along with the downregulated expression of OCT4, were reversed by the concurrent inhibition of miR­145. The luciferase assay revealed that the activity of the wild­type OCT4 3' untranslated region reporter was suppressed. This suppression diminished when the miR­145 response element mutated. These findings suggest an undescribed regulatory pathway in PCa, by which TR4 directly suppressed the expression of miR­145, thereby inhibiting its direct target OCT4, leading to the promotion of chemoresistance in PCa.