Protocadherins are cell-cell adhesion molecules encoded by a large family of genes.
Recent reports demonstrate recurrent silencing of protocadherin genes in tumors and
provide strong arguments for their tumor supresor functionality. Loss of protocadherins
may contribute to cancer development not only by altering cell-cell
adhesion, that is a hallmark of cancer, but also by enhancing proliferation and epithelial
mesenchymal transition of cells via deregulation of the WNTsignaling pathway. In this
study we have further corroborated our previous findings on the involvement of
PCDH17 in laryngeal squamous cell carcinoma (LSCC).Weused bisulfite pyrosequencing
to analyze a cohort of primary LSCC tumors for alterations in PCDH17 promoter
DNA methylation as an alternative gene inactivation mechanism to the homozygous
deletions reported earlier. Moreover, we analyzed primary LSCC samples by
immunohistochemistry for PCDH17 protein loss. We identified recurrent elevation
of PCDH17 promoter DNA methylation in 32/81 (40%) primary tumors (P < 0.001) and
therein hypermethylation of 12 (15%) cases in contrast to no tumor controls (n = 24)
that were all unmethylated. Importantly, DNA demethylation by decitabine has
restored low level PCDH17 expression in LSCC cell lines. In conclusion, we provide a
mechanistic explanation of recurrently observed PCDH17 silencing in LSCC by
demonstrating the role of promoter methylation in this process. In light of these
findings and recent reports showing thatPCDH17methylation is detectable in serum of
cancer patients we suggest that testing PCDH17 DNA methylation might serve as a
potential biomarker in LSCC.