Abstract
BackgroundThe p23.2 region of human chromosome 8 is frequently deleted in several types of epithelial cancer and those deletions appear to be associated with poor prognosis. Cub and Sushi Multiple Domains 1 (CSMD1) was positionally cloned as a candidate for the 8p23 suppressor but point mutations in this gene are rare relative to the frequency of allelic loss. In an effort to identify alternative mechanisms of inactivation, we have characterized CSMD1 expression and epigenetic modifications in head and neck squamous cell carcinoma cell lines.ResultsOnly one of the 20 cell lines examined appears to express a structurally normal CSMD1 transcript. The rest express transcripts which either lack internal exons, terminate abnormally or initiate at cryptic promoters. None of these truncated transcripts is predicted to encode a functional CSMD1 protein. Cell lines that express little or no CSMD1 RNA exhibit DNA methylation of a specific region of the CpG island surrounding CSMD1's first exon.ConclusionCorrelating methylation patterns and expression suggests that it is modification of the genomic DNA preceding the first exon that is associated with gene silencing and that methylation of CpG dinucleotides further 3' does not contribute to inactivation of the gene. Taken together, the cell line data suggest that epigenetic silencing and aberrant splicing rather than point mutations may be contributing to the reduction in CSMD1 expression in squamous cancers. These mechanisms can now serve as a focus for further analysis of primary squamous cancers.
Highlights
The p23.2 region of human chromosome 8 is frequently deleted in several types of epithelial cancer and those deletions appear to be associated with poor prognosis
Cub and Sushi Multiple Domains 1 (CSMD1) promoter methylation in HNSCC cell lines is correlated with expression levels Preliminary evidence suggested that CSMD1 expression is lost in head and neck squamous cell carcinomas [1] but that point mutations were rare [[16], and Schmidt, Richter and Scholnick, unpublished]
Only two of the 20 cell lines we have tested for CSMD1 expression, UPCI:SCC066 and PCI-13, express large transcripts initiated at the normal CSMD1 promoter
Summary
The p23.2 region of human chromosome 8 is frequently deleted in several types of epithelial cancer and those deletions appear to be associated with poor prognosis. CUB and Sushi Multiple Domains 1 (CSMD1) was cloned as a candidate tumor suppressor or progression gene from a region of human chromosome 8 deleted in tumors of the upper aerodigestive tract, prostate, ovary and bladder [17]. Deletion of 8p23.2 or reduced expression of CSMD1 has been associated with poor prognosis in head and neck squamous cell carcinomas and in prostate cancers [2,5,8]. CSMD1, consisting of 70 exons spread over two megabases of 8p23.2, encodes a rare 11.5 kb transcript most abundantly expressed in the brain [1] It is the founding member of a novel, evolutionarily highly conserved gene family whose proteins contain multiple domains thought to be sites of protein-protein or protein-ligand interactions and whose structure suggests that they may be transmembrane receptors or adhesion proteins [9,10]. Transcription of CSMD1 is from left to right in the figure
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