Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer.
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.
Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University Jena Ziegelmühlenweg 1, Jena, Germany.
Linlin
L
Yang
Yuan
Y
Chen
Tiantian
T
Cui
Thomas
T
Knösel
Qing
Q
Zhang
Kai Frederik
KF
Albring
Otmar
O
Huber
Iver
I
Petersen
D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
D051180:Desmoplakins; D025521:Tumor Suppressor Proteins