Development of gene therapy for gastrointestinal cancers by using c-myc transcriptional suppressor FUSE Binding Protein-Interacting Repressor, FIR

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Elevated expression of c-myc has been detected in a broad range of human cancers, indicating a key role for this oncogene in tumor development. Recently, an interaction between FIR (FBP Interacting Repressor) and TFIIH/p89/XPB helicase was found to repress c-myc transcription and so might be important for suppressing tumor formation. In this study, we showed that enforced expression of FIR induced apoptosis. Deletion of FIR's amino terminal repression domain rescued the cells from apoptosis, as did co-expression of c-Myc with FIR ; thus repression of Myc mediates FIR-driven apoptosis. Surprisingly, a splicing variant of FIR unable to repress c-myc nor to drive apoptosis was frequently discovered in human primary colorectal cancers, but not in the adjacent normal tissues. Coexpression of this splicing variant with repressor-competent FIR, either in HeLa cells or in the colon cancer cell line SW480,not only abrogated c-Myc suppression but inhibited apoptosis. These results strongly suggest the expression of this splicing variant promotes tumor development by disabling FIR-repression and so sustaining high levels of c-Myc and opposing apoptosis in colorectal cancer. One route to the development of cancer therapies directed against c-Myc may go through FIR and its variants