title: 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.
authors.affiliation: Department of Pathology, College of Medicine, and.
authors.forename: Hey-Yon
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, and.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Won
authors.affiliation: Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Korea gkong@hanyang.ac.kr jy2jy2@hanyang.ac.kr.
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, and Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Korea gkong@hanyang.ac.kr jy2jy2@hanyang.ac.kr.
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C503627:CBX7 protein, human; C495270:CTNNB1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051820:TCF Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D063150:Polycomb Repressive Complex 1
keywords: acetylation; p300; polycomb; self-renewal pathway