KAP1 promotes proliferation and metastatic progression of breast cancer cells

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 fa...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 75; no. 2; pp. 344 - 355
Main Authors:	Addison, Joseph B, Koontz, Colton, Fugett, James H, Creighton, Chad J, Chen, Dongquan, Farrugia, Mark K, Padon, Renata R, Voronkova, Maria A, McLaughlin, Sarah L, Livengood, Ryan H, Lin, Chen-Chung, Ruppert, J Michael, Pugacheva, Elena N, Ivanov, Alexey V
Format:	Journal Article
Language:	English
Published:	United States 15-01-2015
Subjects:	Amino Acid Sequence Animals Antibodies - immunology Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Growth Processes - physiology Cell Line, Tumor Chickens Disease Progression Female Gene Knockdown Techniques Heterografts Humans Mice Mice, Inbred NOD Molecular Sequence Data Neoplasm Metastasis Proteasome Endopeptidase Complex - metabolism Repressor Proteins - biosynthesis Repressor Proteins - genetics Repressor Proteins - immunology Repressor Proteins - metabolism RNA, Messenger - biosynthesis RNA, Messenger - genetics Sumoylation Tripartite Motif-Containing Protein 28 Up-Regulation Zinc Fingers
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-14-1561