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Page 10 of 17 Matsushita et al. Hepatoma Res 2018;4:61 I http://dx.doi.org/10.20517/2394-5079.2018.81

Table 1. Summaries of studies in far-upstream element-binding protein (FUBP1)/far upstream element-binding protein-
interacting repressor (FIR)/FIRDexon2/poly (U)-binding-splicing factor (PUF60) system related to human diseases
Targets Functions References
[3,4,7] (far-upstream element
c-Myc gene transcriptiona activator
(FUSE)/FUBP1)
c-Myc gene transcriptiona repressor [8] (FIR)
Apoptosis induction [4,10-14] (FIR)
Dominant negative of FIR splicing variant [16,22,30,38] (FIRΔexon2)
PKM2/Cancer metabolism [50]
DNA damage/cell cycle [18-20,29-31,46]
T-cell type acute lymphoblastic leukemia [43,50]
1 Cancers in general
SAP155(SF3B1)-FIR(PUF60) interaction in alternative splicing of mRNAs [23,29,31,40-42]
F-box and WD repeat domain-containing 7 (FBW7)/proteosome [44,45]
autoandibodies/immune reaction [21,24,25,27,28]
Alternative splicing of mRNAs [17-19,21-24,33,34]
E-caherin/invasion/metastasis, Epithelial mesenchymal transition (EMT) [52]
[5,6,56,57] (FUBP1),[9,38,43]
carcinobgenesis
(FIRΔexon2)
tolerance for hypoxia [53]
2 Hepatoma proliferation, migration, cancer metabolism, signal transduction, [6,18,38,51,56,57]
covalantly closed circular DNA (cccDNA of HCV) [34]
ENI/ENII enhancer region [34]
Hepatitis B virus (HBV)/
3 HBV core promotor [34]
hepatitis C virus (HCV)
spliced RNA (HBV RNA) [17]
HCV [55]
CHARGE syndrome [59]
Phenotypic variability of genetic diseases [59]
Verheji syndrome [59,60]
developmental delay, intelllectual disability, microcephaly, craniofacial, [58,59]
renal and cardiac defects
Eye coloboma and complex cardiac malformations [59,61]
4 Rare disease
atrioventricular septal defect and hypoplastic aortic arch, facial
dysmorphism, microretrognathia, dysmorphic ears, clinodactyly of the 5th
digit on both hands, mild rocker bottom feet and abnormal third sacral [61,62]
vertebra
microcephaly, short stature, intellectual disability, and heart defects with
a de novo c.505C > T variant leading to a p.His169Tyr change in PUF60. [63-65]
(PUF60 deficiency)

in the degron pocket (W425 D399 in the 3D-structure) [Figure 3]. Together, simultaneous downregulation
of FBW7 and E-cadherin is potentially pivotal for invasion or metastasis of cancers through EMT and may
also contribute to therapeutic target for cancers. Clinically, BK697 and its derivatives are potential candidate
anticancer drugs for cancers targeting FBW7 and E-cadherin suppression.

DISCUSSION
This study demonstrated that FIR strongly repressed endogenous c-Myc transcription and induced apoptosis.
Most importantly, a splicing variant of FIR, FIRΔexon2, found frequently in human primary colorectal
cancer tissue, not only lacked the c-Myc-suppressing and apoptosis-inducing action of FIR, but prevented
normal FIR from performing these activities. Thus FIRΔexon2 may contribute to tumor progression by
enabling higher levels of c-Myc expression and greater resistance to apoptosis in tumors than in normal
cell [Figure 2A]. The value of FIR and/or FIRΔexon2 detection for cancer diagnosis is under investigation.
Recently, PUF60, another FIR splicing variant having exon 5, directly binds to splicing factor SF3B1 with
[39]
UHM and inhibition of SF3B (SAP155 is a subunit of SF3B) by natural chemicals demonstrated strong
[53]
antitumor effect [Figure 2B] [32,33] . Hypoxia leads to AS of FIR/PUF60 and in PC3 prostate cancer cells .
Given the central role of c-Myc in the development of many cancers, and inhibition of splicing function
of PUF60 (or FIR itself) with SF3B indicates strong antitumor activity, one route to the development of