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, 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 to sustain high levels of c-Myc and oppose apoptosis in colorectal cancer.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]