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ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.

Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J, Yuan J, Wang M, Chen D, Sun Y, Woodward WA, Liu Y, Dean DC, Liang H, Hu Y, Ang KK, Hung MC, Chen J, Ma L - Nat. Cell Biol. (2014)

Bottom Line: However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties.Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response.These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

ABSTRACT
Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

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ZEB1 correlates with CHK1 protein levels and poor clinical outcome in humanbreast cancer(a) Immunohistochemical staining of ZEB1 and CHK1 in representativecarcinoma specimens on the NCI breast cancer progression tissue microarrays.Brown staining indicates positive immunoreactivity. Scale bar: 50μm.(b) Correlation between ZEB1 and CHK1 protein levels in human breasttumors. Statistical significance was determined by aχ2 test. R is thecorrelation coefficient.(c) Kaplan-Meier curves showing the distant relapse-free survival ofpatients with high or low expression of ZEB1 in their breast tumors. Statisticalsignificance was determined by a log-rank test.(d) The working model of regulation of radiosensitivity and DDR byZEB1.
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Figure 8: ZEB1 correlates with CHK1 protein levels and poor clinical outcome in humanbreast cancer(a) Immunohistochemical staining of ZEB1 and CHK1 in representativecarcinoma specimens on the NCI breast cancer progression tissue microarrays.Brown staining indicates positive immunoreactivity. Scale bar: 50μm.(b) Correlation between ZEB1 and CHK1 protein levels in human breasttumors. Statistical significance was determined by aχ2 test. R is thecorrelation coefficient.(c) Kaplan-Meier curves showing the distant relapse-free survival ofpatients with high or low expression of ZEB1 in their breast tumors. Statisticalsignificance was determined by a log-rank test.(d) The working model of regulation of radiosensitivity and DDR byZEB1.

Mentions: To validate the association between CHK1 and ZEB1 in breast cancerpatients, we performed immunohistochemical staining of these two proteins (Fig. 8a) on the breast cancer progressiontissue microarrays from the National Cancer Institute51. A highly significant positivecorrelation (R = 0.43, P < 1× 10−6) between CHK1 and ZEB1 was observed in thesebreast carcinomas, in which 69% (89 of 129) of the tumors with high ZEB1expression exhibited high CHK1 expression, and 77% (47 of 61) of thetumors with low ZEB1 expression showed low CHK1 expression (Fig. 8b).


ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.

Zhang P, Wei Y, Wang L, Debeb BG, Yuan Y, Zhang J, Yuan J, Wang M, Chen D, Sun Y, Woodward WA, Liu Y, Dean DC, Liang H, Hu Y, Ang KK, Hung MC, Chen J, Ma L - Nat. Cell Biol. (2014)

ZEB1 correlates with CHK1 protein levels and poor clinical outcome in humanbreast cancer(a) Immunohistochemical staining of ZEB1 and CHK1 in representativecarcinoma specimens on the NCI breast cancer progression tissue microarrays.Brown staining indicates positive immunoreactivity. Scale bar: 50μm.(b) Correlation between ZEB1 and CHK1 protein levels in human breasttumors. Statistical significance was determined by aχ2 test. R is thecorrelation coefficient.(c) Kaplan-Meier curves showing the distant relapse-free survival ofpatients with high or low expression of ZEB1 in their breast tumors. Statisticalsignificance was determined by a log-rank test.(d) The working model of regulation of radiosensitivity and DDR byZEB1.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4150825&req=5

Figure 8: ZEB1 correlates with CHK1 protein levels and poor clinical outcome in humanbreast cancer(a) Immunohistochemical staining of ZEB1 and CHK1 in representativecarcinoma specimens on the NCI breast cancer progression tissue microarrays.Brown staining indicates positive immunoreactivity. Scale bar: 50μm.(b) Correlation between ZEB1 and CHK1 protein levels in human breasttumors. Statistical significance was determined by aχ2 test. R is thecorrelation coefficient.(c) Kaplan-Meier curves showing the distant relapse-free survival ofpatients with high or low expression of ZEB1 in their breast tumors. Statisticalsignificance was determined by a log-rank test.(d) The working model of regulation of radiosensitivity and DDR byZEB1.
Mentions: To validate the association between CHK1 and ZEB1 in breast cancerpatients, we performed immunohistochemical staining of these two proteins (Fig. 8a) on the breast cancer progressiontissue microarrays from the National Cancer Institute51. A highly significant positivecorrelation (R = 0.43, P < 1× 10−6) between CHK1 and ZEB1 was observed in thesebreast carcinomas, in which 69% (89 of 129) of the tumors with high ZEB1expression exhibited high CHK1 expression, and 77% (47 of 61) of thetumors with low ZEB1 expression showed low CHK1 expression (Fig. 8b).

Bottom Line: However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties.Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response.These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

ABSTRACT
Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.

Show MeSH
Related in: MedlinePlus