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Matsushita et al. Hepatoma Res 2018;4:61 I http://dx.doi.org/10.20517/2394-5079.2018.81 Page 5 of 17

A

B

Figure 2. (A) 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. Far upstream element-binding protein-interacting repressor (FIR) gen and c-Myc gene locates at 8q24.3. An
interaction between FIR (FBP interacting repressor) and transcriptional factor IIH helicase was found to repress c-Myc transcription
and so might be important for suppressing tumor formation. FIR is alternatively spliced in colorectal cancer lacking the transcriptional
repression domain within exon 2 (FIRΔexon2) that inhibit FIR as a dominant negative form of FIR. FIRΔexon2 potently forms a
heterodimer with FIR and thus FIRΔexon2 interferes with FIR to bind to far upstream element of c-Myc promoter where FIR binds. FIR and
FIRΔexon2 form a homo- or hetero-dimer, which makes a complex with SAP155. SAP155 is a subunit of the essential splicing factor 3B
(SF3B) subcomplex in the spliceosome. The interaction between SAP155 and FIR/FIRΔexon2 potentially integrated cell cycle progression
and c-Myc transcription through P89 suppression; (B) FIR/FIRΔexon2/SAP155 interaction is pivotal for cancer development and
differentiation and is thus a potent target for cancer screening and treatment. These results strongly suggest that FIRΔexon2 antagonized
FIR in c-Myc transcriptional suppression and simultaneously interferes with SF3B in splicing during tumor progression. Importantly,
Spliceostatin A that is a strong chemical inhibitor of SF3B resulted in c-Myc overexpression probably due to the FIR downregulation. FIR:
FUBP1-interacting repressor