Title

A Novel Role of Kruppel-like Factor 8 in DNA Repair in Breast Cancer Cells

Authors

Authors

H. Lu; L. Hu; T. S. Li; S. Lahiri; C. Shen; M. S. Wason; D. Mukherjee; H. Xie; L. Yu;J. H. Zhao

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

FOCAL ADHESION KINASE; CYCLIN D1; KLF8 TRANSCRIPTION; GENOMIC STABILITY; DAMAGE RESPONSE; EXCISION-REPAIR; ACTIVATION; PROTEIN; PARP-1; IDENTIFICATION; Biochemistry & Molecular Biology

Abstract

Kruppel-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 inDNArepair 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 gamma H2A.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.

Journal Title

Journal of Biological Chemistry

Volume

287

Issue/Number

52

Publication Date

1-1-2012

Document Type

Article

Language

English

First Page

43720

Last Page

43729

WOS Identifier

WOS:000312940800051

ISSN

0021-9258

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