TR4 nuclear receptor alters the prostate cancer CD133+ stem/progenitor cell invasion via modulating the EZH2-related metastasis gene expression

摘要

The testicular nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily that mediates various biological functions with key impacts on metabolic disorders and tumor progression. Here we demonstrate that TR4 may play a positive role in prostate cancer (PCa) CD133+ stem/progenitor (S/P) cell invasion. Targeting TR4 with lentiviral silencing RNA significantly suppressed PCa CD133+ S/P cell invasion both in vitro and in vivo. Mechanism dissection found that TR4 transcriptionally regulates the oncogene EZH2 via binding to its 5′ promoter region. The consequences of targeting TR4 to suppress EZH2 expression may then suppress the expression of its downstream key metastasis-related genes including NOTCH1, TGFβ1, SLUG and MMP9. Rescue approaches via adding the EZH2 reversed the TR4-mediated PCa S/P cell invasion. Together, these results suggest that the TR4→EZH2 signaling may play a critical role in the PCa S/P cell invasion and may allow us to develop a better therapy to battle the PCa metastasis.