Epigenetically regulated PCDHB15 impairs aggressiveness of metastatic melanoma cells

Abstract

The protocadherin proteins are cell adhesion molecules at the crossroad of signaling pathways playing a major role in neuronal development. It is now understood that their role as signaling hubs is not only important for the normal physiology of cells but also for the regulation of hallmarks of cancerogenesis. Importantly, protocadherins form a cluster of genes that are regulated by DNA methylation. We have identified for the first time that PCDHB15 gene is DNA-hypermethylated on its unique exon in the metastatic melanoma-derived cell lines and patients’ metastases compared to primary tumors. This DNA hypermethylation silences the gene, and treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine reinduces its expression. We explored the role of PCDHB15 in melanoma aggressiveness and showed that overexpression impairs invasiveness and aggregation of metastatic melanoma cells in vitro and formation of lung metastasis in vivo. These findings highlight important modifications of the methylation of the PCDHβ genes in melanoma and support a functional role of PCDHB15 silencing in melanoma aggressiveness.

A Bioinformatics Analysis of Ovarian Cancer Data Using Machine Learning

“…For PCDHB15, a similar aggressive behavior was identified. It has been shown that overexpression in melanoma leads to invasiveness and aggregation of metastatic melanoma in vitro and forming lung metastasis in vivo [71]. Taken together, we suggest that both genes alter the biological process of cell-cell adhesion and the process of plasma membrane adhesion molecules [72].…”

Elucidating Novel Targets for Ovarian Cancer Antibody–Drug Conjugate Development: Integrating In Silico Prediction and Surface Plasmon Resonance to Identify Targets with Enhanced Antibody Internalization Capacity

“…PCDHB10 and PCDHB15 are members of the cadherin superfamily of calcium-dependent cell–cell adhesion molecules; PCDHB10 is involved in the establishment and maintenance of neuronal functions in the brain and is implicated in paediatric malignancies [ 40 ]. PCDHB15 is involved in cell adhesion, and it is epigenetically regulated in melanoma and breast cancer cells [ 41 , 42 ]. Furthermore, OPRK1 has been implicated in facilitating the migration of breast cancer cells, while the low expression of GABRB1 correlated with a poor prognosis in colon adenocarcinoma [ 43 , 44 ].…”

“…However, similar to PCDHB10, it has been reported as a tumour suppressor. Nonetheless, like other cell adhesion proteins altered in specific cancer types, PCDHB15 can promote cancer cell proliferation and migration [ 41 , 42 , 43 , 51 ]. In vivo experiments have shown that PCDHB15 overexpression in melanoma promote cell invasion, cancer cell aggregation, and lung metastasis [ 43 ].…”