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DUSP6 regulates drug sensitivity by modulating DNA damage response

Bagnyukova, T.V.
; 
Restifo, D.
; 
Beeharry, N.
; 
Gabitova, L.
; 
Li, T.
; 
Serebriiskii, Ilya G.
; ; 
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Genre
Journal article
Date
2013-07-09
Advisor
Committee member
Group
Fox Chase Cancer Center (Temple University)
Department
Cancer and Cellular Biology
Subject
DUSP6
 DNA damage response
 Drug sensitivity
 EGFR
 EGFR inhibitors
 Sensitivity to apoptosis
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http://hdl.handle.net/20.500.12613/9237
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GolemisEtAl-JournalArticle-2013-07.pdf
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DOI
http://dx.doi.org/10.1038/bjc.2013.353
Abstract
Background: Dual specificity phosphatase 6 (DUSP6) is a member of a family of mitogen-activated protein kinase phosphatases that dephosphorylates and inhibits activated ERK1/2. Dual specificity phosphatase 6 is dynamically regulated in developmental and pathological conditions such as cancer. Methods: Cancer cell lines were made deficient in DUSP6 by siRNA and shRNA silencing. Sensitivity to anti-EGFR and chemotherapeutic agents was determined in viability and apoptosis assays, and in xenografts established in SCID mice. Cellular effects of DUSP6 inactivation were analysed by proteomic methods, followed by analysis of markers of DNA damage response (DDR) and cell cycle. Results: We determined that depletion of DUSP6 reduced the viability of cancer cell lines and increased the cytotoxicity of EGFR and other targeted inhibitors, and cytotoxic agents, in vitro and in vivo. Subsequent phosphoproteomic analysis indicated DUSP6 depletion significantly activated CHEK2 and p38, which function in the DDR pathway, and elevated levels of phosphorylated H2AX, ATM, and CHEK2, for the first time identifying a role for DUSP6 in regulating DDR. Conclusion: Our results provide a novel insight into the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer.
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Citation
Bagnyukova TV, Restifo D, Beeharry N, Gabitova L, Li T, Serebriiskii IG, Golemis EA, Astsaturov I. DUSP6 regulates drug sensitivity by modulating DNA damage response. Br J Cancer. 2013 Jul 9;109:1063–1071. doi:10.1038/bjc.2013.353.
Citation to related work
Springer Nature
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British Journal of Cancer, Vol. 109
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