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: Joseph B Addison, Colton Koontz, James H Fugett, Chad J Creighton, Dongquan Chen, Mark K Farrugia, Renata R Padon, Maria A Voronkova, Sarah L McLaughlin, Ryan H Livengood, Chen-Chung Lin, J Michael Ruppert, Elena N Pugacheva, Alexey V Ivanov
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 2 Pg. 344-55 (Jan 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25421577 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies
• RNA, Messenger
• Repressor Proteins
• ZNF350 protein, human
• TRIM28 protein, human
• Tripartite Motif-Containing Protein 28
• Proteasome Endopeptidase Complex

Topics

• Amino Acid Sequence
• Animals
• Antibodies (immunology)
• Breast Neoplasms (genetics, metabolism, 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)
• RNA, Messenger (biosynthesis, genetics)
• Repressor Proteins (biosynthesis, genetics, immunology, metabolism)
• Sumoylation
• Tripartite Motif-Containing Protein 28
• Up-Regulation
• Zinc Fingers