The p53 target gene desmocollin 3 acts as a novel tumor suppressor through inhibiting EGFR/ERK pathway in human lung cancer

Abstract

Desmosomes are intercellular junctions that confer strong cell-cell adhesion. Altered expression of desmocollin 3 (DSC3), a member of the desmosomal cadherin family, was found in various cancers; however, its functional involvement in carcinogenesis has not yet been elucidated. Expression/localization of DSC3 was analyzed by real-time reverse transcription-PCR, western blotting, immunofluorescence and immunohistochemistry. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR and bisulfite sequencing. It turned out that downregulation of DSC3 in lung cancer cells was associated with DNA hypermethylation. In primary lung tumors, DSC3 was a potential diagnostic marker for lung squamous cell carcinoma, and DSC3 DNA hypermethylation was correlated with poor clinical outcome. To investigate the effect of the tumor suppressor gene p53 on DSC3, transient transfection with a wild-type p53-expression vector was performed. Overexpression of p53 resulted in an increased expression of DSC3 in a DSC3-unmethylated lung cancer cell line H2170, but not in H1299, a DSC3-methylated cell line. However, combination of p53 transfection with demethylation agent 5-aza-2'-deoxycytidine treatment led to increased expression of DSC3 in H1299 cells. Furthermore, functional studies after stable transfection of a DSC3 expression vector showed that ectopic expression of DSC3 inhibited cell proliferation, anchorage-independent growth, migration, as well as invasion, and most interestingly led to reduced phosphorylation levels of extracellular signal-regulated kinase1/2. Taken together, our data suggested that DSC3 acts as a novel tumor suppressor gene through inhibition of epidermal growth factor receptor/extracellular signal-regulated kinase signaling in lung cancer cells.

Structural and Functional Diversity of Desmosomes

“…While this example and others (Goonesinghe et al, 2012;Gehmlich et al, 2012;Cui et al, 2012;Den et al, 2006;Kolegraff et al, 2011;Chen et al, 2013) illustrated the broad impact of desmogleindesmocollin expression on organismal development and tissue homeostasis, much of the information pertaining to desmosomal cadherins and signaling stems from the study of a specifi c tissue, the epidermis. As noted above, the epidermis expresses all desmocollin and desmoglein isoforms, but does so in a manner which depends heavily upon the differentiation status of keratinocytes.…”

Desmocollin-3 and Cancer

“…DSC3 is one of the p53-responsive gene [1][2][3][4][5][6][7][8][9][10][11]. p53 is reported to be an upstream to DSC3.…”

“…p53 expression in cancer is known to be altered by mutation or deletion of the p53 gene, with mutation of p53 being the most common event in human cancer [12]. Besides deletion and mutation of p53, p53 target genes are also silenced by epigenetic silencing like DNA methylation [1][2][3][4][5][6][7][8][9][10][11]. Mutant p53 inactivates p63 and is also associated with down regulation of DSC3 [10].…”

“…DNA damaging agents: Expression of wild type of p53 can also be increased or induced by DNA damaging agents like radiotherapy, doxorubicin, cisplatin, paclitaxel, gemcitabine etc. Expressionof wild type p53 is sufficient to induce expression of DSC3 in breast, colorectal and lung cancers in absence of DSC3 DNA methylation [1,10,11]. Expression of wild typep53 converts DSC3 negative tumors in to DSC3 positive.…”

“…Desmocollin-3[DSC3] is one of the adhesion molecules of cadher in super family found in desmosome and is a major adhesive force of epithelial cells [1][2][3][4][5][6]. DSC3 is a transmembrane calcium-dependent glycoprotein produced by the endoplasmic reticulum,encoded by the DSC3 gene.…”