CHES1/FOXN3 interacts with Ski-interacting protein and acts as a transcriptional repressor

Checkpoint Suppressor 1 (CHES1; FOXN3) encodes a member of the forkhead/winged-helix transcription factor family. The human CHES1 cDNA was originally identified by its ability to function as a high-copy suppressor of multiple checkpoint mutants of Saccharomyces cerevisiae. Accumulating expression profile data suggest that CHES1 plays a role in tumorigenicity and responses to cancer treatments, though nothing is known regarding the transcriptional function of CHES1 or other FOXN proteins in human cells. In this report, we find that the carboxyl terminus of CHES1 fused to a heterologous DNA binding domain consistently represses reporter gene transcription in cell lines derived from tumor tissues. Using a cytoplasmic two-hybrid screening approach, we find that this portion of CHES1 interacts with Ski-interacting protein (SKIP; NCoA-62), which is a transcriptional co-regulator known to associate with repressor complexes. We verify this interaction through co-immunoprecipitation experiments performed in mammalian cells. Further analysis of the CHES1/SKIP interaction indicates that CHES1 binds to a region within the final 66 hydrophobic residues of SKIP thus defining a new protein-protein interaction domain of SKIP. These data suggest that CHES1 recruits SKIP to repress genes important for tumorigenesis and the response to cancer treatments.