CBX7 inhibits breast tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway.

Abstract

Polycomb protein chromobox homolog 7 (CBX7) is involved in several biologic processes including stem cell regulation and cancer development, but its roles in breast cancer remain unknown. Here, we demonstrate that CBX7 negatively regulates breast tumor initiation. CD44(+)/CD24(-)/ESA(+) breast stem-like cells showed diminished CBX7 expression. Furthermore, small hairpin RNA-mediated CBX7 knockdown in breast epithelial and cancer cells increased the CD44(+)/CD24(-)/ESA(+) cell population and reinforced in vitro self-renewal and in vivo tumor-initiating ability. Similarly, CBX7 overexpression repressed these effects. We also found that CBX7 inhibits the Wnt/β-catenin/T cell factor pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist. In particular, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of the DKK-1 promoter. Furthermore, pharmacologic inhibition of DKK-1 in CBX7-overexpressing cells showed recovery of Wnt signaling and consequent rescue of the CD44(+)/CD24(-)/ESA(+) cell population. Taken together, these findings indicate that CBX7-mediated epigenetic induction of DKK-1 is crucial for the inhibition of breast tumorigenicity, suggesting that CBX7 could be a potential tumor suppressor in human breast cancer.