Abstract
Although the differentiation of oncogenically transformed basal progenitor cells is one of the key steps in prostate tumori- genesis, the mechanisms mediating this cellular process are still largely unknown. Here we demonstrate that an expanded p63 and CK5 basal/progenitor cell population, induced by the con- comitant activation of oncogenic Kras(G12D) and androgen receptor (AR) signaling, underwent cell differentiation in vivo. The differentiation process led to suppression of p63-express- ing cells with a decreased number of CK5 basal cells but an increase of CK8 luminal tumorigenic cells and revealed a hier- archal lineage pattern consisting of p63/CK5 progenitor, CK5/CK8 transitional progenitor, and CK8 differentiated luminal cells. Further analysis of the phenotype showed that Kras-AR axis-induced tumorigenesis was mediated by Gli tran- scription factors. Combined blocking of the activators of this family of proteins (Gli1 and Gli2) inhibited the proliferation of p63 and CK5 basal/progenitor cells and development of tumors. Finally, we identified that Gli1 and Gli2 exhibited dif- ferent functions in the regulation of p63 expression or prolifer- ation of p63 cells in Kras-AR driven tumors. Gli2, but not Gli1, transcriptionally regulated the expression levels of p63 and prostate sphere formation. Our study provides evidence of a novel mechanism mediating pathological dysregulation of basal/progenitor cells through the differential activation of the Gli transcription factors. Also, these findings define Gli proteins as new downstream mediators of the Kras-AR axis in prostate carcinogenesis and open a potential therapeutic avenue of tar- geting prostate cancer progression by inhibiting Gli signaling.
