Document Detail


A novel role of Krüppel-like factor 8 in DNA repair in breast cancer cells.
MedLine Citation:
PMID:  23105099     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Krüppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, the role of KLF8 in cancer remains largely unknown. Here, we report a surprisingly novel role for KLF8 in DNA repair in breast cancer cells. Comet, clonogenic, and WST-1 assays showed that KLF8 expression is required for protecting human breast cancer cells from doxorubicin-induced DNA damage and cell death. Western blotting indicated that overexpression of ectopic KLF8 attenuated the levels of the DNA damage marker γH2A.X in doxorubicin-treated PARP-1(+/+) but not PARP-1(-/-) mouse embryonic fibroblasts, whereas the PARP-1-binding-defective KLF8 mutant failed to do so. Interestingly, in response to the DNA damage, KLF8 was phosphorylated by the DNA-dependent protein kinase catalytic subunit and, subsequently, SUMOylated by SUMO E3 ligases protein inhibitors of activated STAT (PIASs), which depends upon the interaction of KLF8 with DNA-dependent protein kinase catalytic subunit, PIASs, and PARP-1 as well as their enzymatic activities. Lastly, we show evidence that KLF8 was recruited to the DNA damage site. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair and therapeutic resistance in breast cancer cells.
Authors:
Heng Lu; Liu Hu; Tianshu Li; Satadru Lahiri; Chao Shen; Melissa S Wason; Debarati Mukherjee; Hui Xie; Lin Yu; Jihe Zhao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-26
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-24     Completed Date:  2013-02-26     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  43720-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / pharmacology*
Breast Neoplasms / drug therapy,  genetics,  metabolism*,  pathology
Cell Line, Tumor
DNA Repair / drug effects*,  genetics
DNA-Activated Protein Kinase / genetics,  metabolism
Doxorubicin / pharmacology*
Drug Resistance, Neoplasm / drug effects*,  genetics
Embryo, Mammalian / metabolism
Fibroblasts / metabolism
Humans
Mice
Mice, Knockout
Neoplasm Proteins / genetics,  metabolism*
Phosphorylation / drug effects,  genetics
Poly(ADP-ribose) Polymerases / genetics,  metabolism
Repressor Proteins / genetics,  metabolism*
Sumoylation / drug effects,  genetics
Transcription Factors / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA132977/CA/NCI NIH HHS; R01 CA132977/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/KLF8 protein, human; 0/Klf8 protein, mouse; 0/Neoplasm Proteins; 0/Repressor Proteins; 0/Transcription Factors; 80168379AG/Doxorubicin; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Parp1 protein, mouse; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.11.1/DNA-Activated Protein Kinase
Comments/Corrections

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