Loss of Special AT-Rich Binding Protein 1 Expression is a Marker of Poor Survival in Lung Cancer

被引:75
作者
Selinger, Christina I. [1 ,2 ]
Cooper, Wendy A. [2 ,3 ]
Al-Sohaily, Sam [1 ]
Mladenova, Dessislava N. [1 ]
Pangon, Laurent [1 ]
Kennedy, Catherine W. [4 ]
McCaughan, Brian C. [5 ]
Stirzaker, Clare [1 ]
Kohonen-Corish, Maija R. J. [1 ,6 ]
机构
[1] Garvan Inst Med Res, Canc Res Program, Sydney, NSW, Australia
[2] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia
[3] Univ Western Sydney, Sch Med, Discipline Pathol, Sydney, NSW, Australia
[4] Strathfield Private Hosp, Dept Surg, Sydney, NSW, Australia
[5] Royal Prince Alfred Hosp, Dept Cardiothorac Surg, Sydney, NSW, Australia
[6] Univ New S Wales, St Vincents Clin Sch, Fac Med, Sydney, NSW, Australia
关键词
SATB1; Lung cancer; Prognostic; Biomarker; DOMAIN-MEDIATED DIMERIZATION; CIGARETTE-SMOKING; GENE-EXPRESSION; CHROMOSOME; 3P; BRONCHIAL EPITHELIUM; HISTOLOGIC TYPE; RISK-ASSESSMENT; GASTRIC-CANCER; BREAST-CANCER; DNA-BINDING;
D O I
10.1097/JTO.0b013e31821b4ce0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Introduction: Lung cancer is the leading cause of cancer-related mortality and requires more effective molecular markers of prognosis and therapeutic responsiveness. Special AT-rich binding protein 1 (SATB1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate hundreds of genes in a tissue-specific manner. Initial studies suggest that SATB1 overexpression is a predictor of poor prognosis in breast cancer, but the prognostic significance of SATB1 expression has not been evaluated in lung cancer. Methods: A cohort of 257 lung cancers was evaluated by immunohistochemistry. Epigenetic silencing of SATB1 was examined in cell lines by 5-Aza 2-deoxycytidine and trichostatin A treatment, and chromatin immunoprecipitation. Results: Significant loss of SATB1 expression was found in squamous preinvasive lesions (p < 0.04) and in non-small cell lung cancers (p < 0.001) compared with matched normal bronchial epithelium. Loss of SATB1 independently predicted poor cancer-specific survival in squamous cell carcinomas (SCCs; hazard ratio: 2.06, 95% confidence interval: 1.2-3.7, p = 0.016). Treatment of lung cancer cell lines with the histone deacetylase inhibitor trichostatin A resulted in up-regulation of SATB1. SATB1 was associated with a decrease in the active chromatin mark acetylated histone H3K9 and an increase in the repressive polycomb mark trimethylated H3K27 in a SCC cell line relative to a normal bronchial epithelial cell line. Conclusions: This is the first study showing that SATB1 expression is lost in early preinvasive squamous lesions and that loss of SATB1 is associated with poor prognosis in lung SCC. We hypothesize that the SATB1 gene is epigenetically silenced through histone modifications.
引用
收藏
页码:1179 / 1189
页数:11
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