Collaboration of Kras and Androgen Receptor Signaling Stimulates EZH2 Expression and Tumor-Propagating Cells in Prostate Cancer

Abstract

Elevation of the chromatin repression factor enhancer of zeste homolog (EZH2) is associated with progression and poor prognosis in several human cancers including prostate cancer. However, the mechanisms driving EZH2 expression are not fully understood. In this study, we investigated the functional synergy in prostate cancers in mice resulting from activation of the androgen receptor, Kras, and Akt, which drives three of the most frequently activated oncogenic signaling pathways in prostate cancer. Although, any two of these three events were sufficient to promote the formation and progression of prostate cancer, only the synergy of androgen receptor and Kras signaling could elevate EZH2 expression and expand prostate cancer progenitor cells in vivo.Our findings have revealed a genetic mechanism resulting in enhanced EZH2 expression during the progression of aggressive prostate cancer, with important implications for understanding how to target advanced disease where cancer progenitor cells may be critical. Cancer Res; 72(18); 4672-81. Ó2012 AACR.

Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

“…Our studies reveal a novel pathway regulating p63 expression and the proliferation of p63-expressing cells through synergy of doxycycline-inducible Kras and AR, two commonly activated oncogenes in prostate cancer (11 …”

“…Because all lentiviral vectors were derived from the FUCRW parental vector, they carry an RFP marker under the CMV promoter. Lentivirus production and infection were performed as described previously (11). All procedures followed the safety guidelines and regulations of the University of Georgia.…”

“…Previous studies have shown that the simultaneous activation of Kras and AR leads to an expansion of basal/progenitor cells (11). To monitor whether pathologically induced p63 ϩ and CK5 ϩ basal/progenitor cells have the potential to differentiate into luminal tumorigenic cells, we used a doxycycline-inducible Kras(G12D) model.…”

“…1D, h) or CK18 ϩ (Fig. 1D, j (11). To evaluate the importance of androgen levels in the oncogenic transformation of basal/progenitors cells, previously isolated Kras(G12D)ϩAR tumorigenic cells were implanted subcutaneously in a secondary recipient with or without an external testosterone pellet.…”

“…Gene fusion, genetic mutation, and prostate carcinogens have been reported in amplification or activation of Ras/Kras oncogenic signaling in prostate cancer (4 -10). We have shown previously that the interplay of oncogenic Kras(G12D) and overexpression of AR signaling promotes prostate tumorigenesis through expansion of basal/progenitor cells (11). However, the molecular mechanisms underlying the transformation of these cells and the differentiation plasticity remain elusive.…”