CBX7 inhibits breast cancer stem cell activity and tumorigenicity through DKK-1-mediated suppression of the Wnt/beta-catenin pathway

Abstract

Chromoprotein homologue 7 (CBX7), a member of the polycomb repressive complex (PRC)-1, has been involved in several biological processes including stem cell regulation and cancer development, but its roles in cancer stem cells (CSCs) and breast tumorigenicity remain unknown. Here, we demonstrated that CBX7 negatively regulates breast CSCs. CD44+/CD24-/ESA+ cells, a population of breast CSCs, showed diminished CBX7 expression compared with non-CSCs. Furthermore, small hairpin RNA (shRNA)-mediated CBX7 knockdown in breast epithelial and cancer cell lines increased breast CSC population and reinforced in vitro self-renewal and in vivo tumor initiating ability. Similarly, CBX7 overexpression showed reduced stemness of breast CSCs. We also found that CBX7 inhibits the Wnt/β-catenin/TCF pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist, to impede self-renewal of breast CSCs. Particularly, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of DKK-1 promoter. Furthermore, pharmacological inhibition of DKK-1 in CBX7 overexpressing cells showed recovery of the Wnt signaling and consequent rescue of breast CSC activity. Taken together, these findings indicated that CBX7-mediated epigenetic induction of DKK-1 is crucial for inhibition of breast CSC activity, suggesting that CBX7 could be a potential tumor suppressor as a novel negative regulator of CSCs in human breast cancer.