DSC3 expression is regulated by p53, and methylation of DSC3 DNA is a prognostic marker in human colorectal cancer

Abstract

Background:Desmocollin 3 (DSC3), a member of the cadherin superfamily and integral component of desmosomes, is involved in carcinogenesis. However, the role of DSC3 in colorectal cancer (CRC) has not yet been established.Methods:Desmocollin 3 expression in CRC cell lines was analysed by RT–PCR and western blotting. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR, and bisulphite sequencing (BS). The regulatory role of p53 was investigated by transfection.Results:Desmocollin 3 was downregulated in CRC cells at mRNA and protein levels. Desmocollin 3 expression was restored in five out of seven cell lines after 5-aza-2′-deoxycytidine (DAC) treatment. A heterogeneous methylation pattern was detected by BS in promoter region and exon 1 of DSC3. Methylation of DSC3 genomic sequences was found in 41% (41 out of 99) of primary CRC, being associated with poor prognosis (P=0.002). Transfection of p53 alone or in combination of DAC increased the DSC3 expression. Similarly, treatment with p53 inducer adriamycin alone or in combination with DAC enhanced DSC3 expression.Conclusions:DNA methylation contributes to downregulation of DSC3 in CRC cell lines. Methylation status of DSC3 DNA is a prognostic marker for CRC. P53 appears to have an important role in regulating DSC3 expression.

Desmosome assembly, homeostasis, and desmosomal disease

“…64 The signaling-related events thought to be involved in the pathomechanisms of PV include not only phosphorylation of Dsg3 and a Ca 2+ /PKC pathway but also apoptosis signaling, as well as modulations of Pg, p38MAPK, heat shock protein 27, cdk2, Src, RhoA, and others. [147][148][149] Overall, research published so far shows that, while desmosome disassembling is a key pathogenic event in pemphigus, the mechanisms by which the splitting occurs involve intracellular signaling pathways possibly triggered by nondesmosomal molecules.…”

Desmocollin-3 and Cancer

“…p53 is reported to be an upstream to DSC3. Expression of DSC3 gene is associated with expression of wild type of p53 and depends on the methylation status of the DSC3 DNA in the p53 binding site [10,11]. 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].…”

“…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].…”

“…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]. p63 is a master regulator of epidermal gene transcription and plays an essential function in controlling epidermal development , cell proliferation, stratification and cell-matrix adhesion [13].…”

“…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.…”