Publications

Abstract

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 organiser that recruits chromatin remodelling proteins to epigenetically regulate hundreds of genes in a tissue-specific manner. SATB1 overexpression is a powerful predictor of poor prognosis in breast cancer, but the significance of SATB1 expression has not been previously evaluated in lung cancer. Results: In a cohort of 285 primary lung cancers, significant loss of SATB1 expression was found in squamous preinvasive lesions (P<0.042) and in non-small cell lung cancers (NSCLC, P<0.001), with adenocarcinomas, squamous cell and large cell carcinomas showing significant loss of expression (P<0.001) compared with matched normal bronchial epithelium. We found that loss of SATB1 independently predicted poor cancer-specific survival in squamous cell carcinomas (SCC; HR 2.06, 95% CI 1.1-3.7, P=0.016). Loss of SATB1 was also significantly associated with poor cancer-specific survival in small cell lung cancers (SCLC; HR 14.48, 95% CI 1.3-164.0, P=0.03), however further investigation of a larger sample is warranted. Treatment of lung cancer cell lines A549 and H520 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 the SCC cell line NCI-H520 cells relative to normal bronchial epithelial cell line NL20 cells. Conclusions: This is the first study showing that SATB1 expression is lost in early preinvasive squamous lesions in the lung and that loss of SATB1 is associated with poor prognosis in lung SCC. Loss of SATB1 expression may be a result of epigenetic silencing caused by histone modifications.