Desmoplakin Has A Tumor Suppressive Function Through Inhibition Of Wnt/Beta-Catenin Signalling Pathway In Human Lung Cancer

Desmosomes are intercellular junctions that confer strong cell-cell adhesion thus provide resistance against mechanical stress on epithelial tissues. A body of evidence indicates that decreased expression of desmosomal proteins is associated with poor prognosis in various cancers. As a key component of desmosomal plaque proteins, the role of desmoplakin (DSP) in lung cancer is not yet elucidated. Here, we investigated the anti-tumourigenic activity of DSP in human non-small cell lung cancer (NSCLC). We found that DSP expression was downregulated in 8 out of 11 lung cancer cell lines and in 34 out of 56 primary lung tumours, and DNA methylation was responsible for gene silencing of DSP in both cell lines and primary lung tumours. Ectopic expression of DSP in NSCLC cell line H157 significantly inhibited cell proliferation, anchorage-independent growth, migration, as well as invasion, and also increased the sensitivity of NSCLC cells to apoptosis induced by an anticancer drug, gemcitabine. Furthermore, overexpression of DSP led to enhanced expression of another desmosomal plaque protein plakoglobin (also called γ-catenin), a competitor of β-catenin, resulting in decreased nuclear β-catenin levels and reduced expression of the Wnt/β-catenin target genes Axin2 and MMP14. Knockdown of DSP by siRNA resulted in downregulation of plakoglobin and upregulation of Axin2 and MMP14. Taken together, our data suggest that DSP is inactivated in lung cancer by DNA methylation, DSP increases the sensitivity to anticancer drug-induced apoptosis, and DSP has tumour suppressive function through inhibition of Wnt/β-catenin signalling pathway in NSCLC. The epigenetic regulation of DSP and its ability to increase the sensitivity to anticancer drug-induced apoptosis imply the clinical application. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 19. doi:1538-7445.AM2012-19