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21764905
Exon 11 skipping of E-cadherin RNA downregulates its expression in head and neck cancer cells.

Mol Cancer Ther, 2011/9;10(9):1751-9.

Sharma S[1], Liao W, Zhou X, Wong DT, Lichtenstein A

Affiliations

PMID: 21764905DOI: 10.1158/1535-7163.MCT-11-0248

Impact factor: 6.009

Abstract
E-cadherin is an important tumor suppressor gene whose expression is lost when cells acquire a metastatic phenotype. We analyzed the role of E-cadherin missplicing as a mechanism of its downregulation by analyzing a misspliced E-cadherin transcript that lacks exon 11 of this gene. This results in a frameshift and a premature termination codon that targets this transcript for degradation. Tumor tissues, including breast (20%, n = 9), prostate (30%, n = 9) and head and neck (75%, n = 8) cancer, express the exon 11-skipped transcripts (vs. nonmalignant controls) and its levels inversely correlate with E-cadherin expression. This is a novel mechanism of E-cadherin downregulation by missplicing in tumor cells, which is observed in highly prevalent human tumors. In the head and neck cancer model, nontumorigenic keratinocytes express exon 11-skipped splice product two- to sixfold lower than the head and neck tumor cell lines. Mechanistic studies reveal that SFRS2 (SC35), a splicing factor, as one of the regulators that increases missplicing and downregulates E-cadherin expression. Furthermore, this splicing factor was found to be overexpressed in 5 of 7 head and neck cell lines and primary head and neck tumors. Also, methylation of E-cadherin gene acts as a regulator of this aberrant splicing process. In 2 head and neck cell lines, wild-type transcript expression increased 16- to 25-folds, whereas the percentage of exon 11-skipped transcripts in both the cell lines decreased five- to 30-folds when cells were treated with a hypomethylating agent, azacytidine. Our findings reveal that promoter methylation and an upregulated splicing factor (SFRS2) are involved in the E-cadherin missplicing in tumors.
MeSH terms
Alternative Splicing; Cadherins; Cell Line, Tumor; DNA Methylation; Exons; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Order; Genetic Vectors; Head and Neck Neoplasms; Humans; Nuclear Proteins; RNA Stability; Ribonucleoproteins; Serine-Arginine Splicing Factors; Transcription, Genetic
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