title: A novel role of Krüppel-like factor 8 in DNA repair in breast cancer cells.
abstract: 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.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, Florida 32827, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Lu
authors.forename: Liu
authors.initials: L
authors.lastname: Hu
authors.forename: Tianshu
authors.initials: T
authors.lastname: Li
authors.forename: Satadru
authors.initials: S
authors.lastname: Lahiri
authors.forename: Chao
authors.initials: C
authors.lastname: Shen
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Wason
authors.forename: Debarati
authors.initials: D
authors.lastname: Mukherjee
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
authors.forename: Jihe
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C507402:KLF8 protein, human; C475812:Klf8 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D004317:Doxorubicin; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase