title: KAP1 promotes proliferation and metastatic progression of breast cancer cells.
abstract: KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here, we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers. KAP1 silencing in breast cancer cells reduced proliferation and inhibited the growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. In cells where KAP1 was silenced, we identified multiple downregulated genes linked to tumor progression and metastasis, including EREG/epiregulin, PTGS2/COX2, MMP1, MMP2, and CD44, along with downregulation of multiple KRAB-ZNF proteins. KAP1-dependent stabilization of KRAB-ZNF required direct interactions with KAP1. Together, our results show that KAP1-mediated stimulation of multiple KRAB-ZNF contributes to the growth and metastasis of breast cancer.
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Addison
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Colton
authors.initials: C
authors.lastname: Koontz
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: James H
authors.initials: JH
authors.lastname: Fugett
authors.affiliation: Department of Medicine and Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Division of Preventive Medicine and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Farrugia
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Renata R
authors.initials: RR
authors.lastname: Padon
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Voronkova
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: McLaughlin
authors.affiliation: Department of Pathology, West Virginia University, Morgantown, West Virginia.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Livengood
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Chen-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ruppert
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
authors.affiliation: Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia. aivanov@hsc.wvu.edu.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ivanov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002645:Chickens; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058207:Sumoylation; D000076183:Tripartite Motif-Containing Protein 28; D015854:Up-Regulation; D016335:Zinc Fingers
chemical_list: D000906:Antibodies; D012333:RNA, Messenger; D012097:Repressor Proteins; C422407:ZNF350 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D046988:Proteasome Endopeptidase Complex