Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer

Abstract

Desmosomes are intercellular junctions that confer strong cell-cell adhesion, thus conferring 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 functional role of desmoplakin (DSP) in cancer is not yet elucidated. Here, we reported the anti-tumorigenic activity of DSP in non-small cell lung cancer (NSCLC). We found by DSP DNA methylation that DSP expression was downregulated in 8 out of 11 lung cancer cell lines and in 34 out of 56 primary lung tumors . Ectopic expression of DSP in the NSCLC cell line H157 significantly inhibited cell proliferation, anchorage-independent growth, migration and invasion and also increased the sensitivity of NSCLC cells to apoptosis induced by an anticancer drug, gemcitabine. Furthermore, overexpression of DSP enhanced expression of plakoglobin (γ-catenin), resulting in decreased T-cell factor/lymphoid enhancer factor (TCF/LEF)-dependent transcriptional activity and reduced expression of the Wnt/β-catenin target genes Axin2 and matrix metalloproteinase MMP14. In accordance, DSP suppression by small interfering RNA resulted in downregulation of plakoglobin and upregulation of β-catenin and MMP14. Taken together, these data suggest that DSP is inactivated in lung cancer by an epigenetic mechanism, increases the sensitivity to anticancer drug-induced apoptosis and has tumor-suppressive function, possibly through inhibition of the Wnt/β-catenin signaling pathway in NSCLC cells. The epigenetic regulation of DSP and its ability to increase the sensitivity to anticancer drug-induced apoptosis has potential implications for clinical application.

Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells

“…The majority of those studies investigated JUP in conjunction with other adhesive junctional proteins and demonstrated that loss of JUP expression, which is an early event in tumorigenesis, in conjunction with the lack of expression of other cell-cell adhesion proteins, such as E-cadherin, α-catenin, β-catenin, DSG, or desmoplakin, resulted in increased tumor formation and size and was correlated with advanced tumor stage, poor patient survival and increased metastasis (29). Decreased expression/loss of desmoplakin and DSG as tumor suppressors was reportedly attributed to invasive tumorigenic potential (9,11). PRP-1 did not exert any effect on occluding/tight junction proteins, such as claudins (data not shown) and E-cadherin (Fig.…”

“…The loss or reduction of one or more desmosome components, including DSG 1-3, DSC 2, DSC 3, JUP, PKP 1-3 and DSP, is observed during development and/or the progression of various human cancers. Adherens junctions and desmosomes are known to be downregulated in cancer, as they exert tumor-suppressive effects (8)(9)(10)(11).…”

Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis

“…Prior studies of DSP in human lung disease indicate that gene expression is decreased in the majority of lung cancer cell lines (14). These cell lines demonstrated hypermethylation in the promoter and intron 1 regions of the gene, indicating that epigenetic mechanisms may regulate DSP gene expression.…”

Alveolar epithelial disintegrity in pulmonary fibrosis

“…DSP has been shown to inhibit Wnt/␤-catenin signaling pathway through regulation of plakoglobin, ␤-catenin, and matrix metalloproteinase 14 in a lung cancer model (65). Aberrant activation of Wnt/␤-catenin signaling pathway has been implicated in the development of pulmonary fibrosis (6) and is, thus, one potential mechanism for a profibrotic role of DSP in IPF.…”