PMID:17909009

Citation	Hucl, T, Brody, JR, Gallmeier, E, Iacobuzio-Donahue, CA, Farrance, IK and Kern, SE (2007) High cancer-specific expression of mesothelin (MSLN) is attributable to an upstream enhancer containing a transcription enhancer factor dependent MCAT motif. Cancer Res. 67:9055-65
Abstract	Identification of genes with cancer-specific overexpression offers the potential to efficiently discover cancer-specific activities in an unbiased manner. We apply this paradigm to study mesothelin (MSLN) overexpression, a nearly ubiquitous, diagnostically and therapeutically useful characteristic of pancreatic cancer. We identified an 18-bp upstream enhancer, termed CanScript, strongly activating transcription from an otherwise weak tissue-nonspecific promoter and operating selectively in cells having aberrantly elevated cancer-specific MSLN transcription. Introducing mutations into CanScript showed two functionally distinct sites: an Sp1-like site and an MCAT element. Gel retardation and chromatin immunoprecipitation assays showed the MCAT element to be bound by transcription enhancer factor (TEF)-1 (TEAD1) in vitro and in vivo. The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments. The cancer specificity seemed to be provided by a putative limiting cofactor of TEF-1 that could be outcompeted by exogenous TEF-1 only in a MSLN-overexpressing cell line. A CanScript concatemer offered enhanced activity. These results identify a TEF family member as a major regulator of MSLN overexpression, a fundamental characteristic of pancreatic and other cancers, perhaps due to an upstream and highly frequent aberrant cellular activity. The CanScript sequence represents a modular element for cancer-specific targeting, potentially suitable for nearly a third of human malignancies.
Links	PubMed Online version:10.1158/0008-5472.CAN-07-0474
Keywords	Base Sequence; Cell Line, Tumor; DNA, Complementary/genetics; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Enhancer Elements, Genetic; GPI-Linked Proteins; HeLa Cells; Humans; Immunohistochemistry; Membrane Glycoproteins/biosynthesis; Membrane Glycoproteins/genetics; Molecular Sequence Data; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Pancreatic Neoplasms/genetics; Pancreatic Neoplasms/metabolism; RNA, Neoplasm/biosynthesis; RNA, Neoplasm/genetics; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Transfection
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