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Epigenomics alternations and dynamic transcriptional changes in
responses to 5-fluorouracil stimulation reveal mechanisms of
acquired drug resistance of colorectal cancer cells
Yifeng Shen1†, Mengsha Tong1†, Qirui Liang1, You Guo2, HuaQin Sun1, Weicheng
Zheng1, Lu Ao1, Zheng Guo1*, Feifei She1*
1
Department of Bioinformatics, Key Laboratory of Ministry of Education for
Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China;
2
Department of Preventive Medicine, School of Basic Medicine Sciences, Gannan
Medical University, Ganzhou, Jiangxi, China.
*Correspondence author to
Feifei She, E-mail: [email protected]
Zheng Guo, E-mail: [email protected]
†These authors contributed equally to this work.
Contents
Supplementary Tables
Supplementary Table S1: 55 ID48 genes detected by either the PFC or PD methods,
which were significantly consistent with CRG5-FU.
Gene ID
Gene Symbol
log2 FC value
AD value
Directiona
9
136
430
701
891
990
1033
1365
2526
2762
3832
3960
4171
4246
4306
4982
5468
5557
5985
6491
6596
7033
7272
7443
9582
9787
9928
9982
10551
10753
11130
23443
26996
29091
51514
51809
54836
55502
NAT1
ADORA2B
ASCL2
BUB1B
CCNB1
CDC6
CDKN3
CLDN3
FUT4
GMDS
KIF11
LGALS4
MCM2
SCGB2A1
NR3C2
TNFRSF11B
PPARG
PRIM1
RFC5
STIL
HLTF
TFF3
TTK
VRK1
APOBEC3B
DLGAP5
KIF14
FGFBP1
AGR2
CAPN9
ZWINT
SLC35A3
GPR160
STXBP6
DTL
GALNT7
BSPRY
HES6
1.02
1.04
1.07
1.17
1.09
1.16
1.08
1.07
1.07
1.06
1.16
1.04
1.03
1.19
1.09
1.68
1.04
1.02
1.01
1.03
1.02
1.08
1.07
1.02
1.08
1.51
1.42
1.30
1.04
1.07
1.02
1.11
1.10
1.06
1.31
1.06
1.06
1.01
8.66
118.97
69.31
89.21
155.70
21.88
43.51
32.39
13.86
25.04
35.01
372.62
0.23
6.70
0.37
39.95
12.01
13.10
13.29
16.16
2.24
288.09
117.72
18.15
36.43
28.22
29.78
346.27
55.79
2.02
113.20
1.84
13.40
1.96
1.55
44.09
9.42
12.01
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
up
64073
64105
79170
79733
81575
84057
84302
139886
148170
149175
152100
222171
340277
100133941
3315
84647
10974
aThe
C19orf33
CENPK
PRR15L
E2F8
APOLD1
MND1
TMEM246
SPIN4
CDC42EP5
MANEAL
CMC1
PRR15
FAM221A
CD24
HSPB1
PLA2G12B
ADIRF
1.04
1.07
1.15
1.02
1.01
1.12
1.03
1.01
1.06
1.10
1.08
1.05
1.15
1.20
1.02
1.07
1.02
446.45
38.16
138.69
5.44
0.29
52.34
1.98
0.72
8.04
42.81
52.85
44.29
1.14
1.68
221.99
1.26
491.66
up
up
up
up
up
up
up
up
up
up
up
up
up
up
down
down
down
direction of DEGs: Each gene was defined as up-regulated (or down-regulated) in
resistant cells compared with parental cells if the value of FC or AD was larger (or smaller)
than zero or one.
Supplementary Table S2: Summaries of the top 20 ID48 genes ranked by PFC
method.
up-regulation
Gene Symbol
Summary
NAT1
N-acetyltransferase 1 (arylamine N-acetyltransferase);
It participates in apoptosis and posttranslational
modification of the proteins; Over-expression of this
gene facilitates cell proliferation independent of the
presence of 5-FU1.
ADORA2B
adenosine A2b receptor; It is a potential therapeutic
target of MRS1754.High expression of this gene
promotes cancer cell growth in colorectal carcinomas2.
ASCL2
achaete-scute family bHLH transcription factor 2;
ASCL2 is a prognostic marker for gastric cancer
patients and it increases cell growth and promotes
resistance to 5-fluorouracil in gastric cancer cells3.
BUB1B
BUB1 mitotic checkpoint serine/threonine kinase B; It
participates in spindle checkpoint function4.
CCNB1
cyclin B1;this gene regulates G2M cell cycle4.
CDC6
cell division cycle 6;
CDKN3
cyclin-dependent kinase inhibitor 3;
CLDN3
claudin 3;
FUT4
fucosyltransferase 4 (alpha (1,3)
fucosyltransferase, myeloid-specific);
GMDS
GDP-mannose 4,6-dehydratase;GMDS regulates the
transition from a primary DISC to a secondary
complex II upon TRAIL or CD95L stimulation5.
KIF11
kinesin family member 11;
LGALS4
lectin, galactoside-binding, soluble, 4;
MCM2
minichromosome maintenance complex component 2;
SCGB2A1
secretoglobin, family 2A, member 1;
NR3C2
nuclear receptor subfamily 3, group C, member 2;
TNFRSF11B
tumor necrosis factor receptor superfamily, member
11b;
PPARG
peroxisome proliferator-activated receptor gamma;
PRIM1
primase, DNA, polypeptide 1 (49kDa);
RFC5
replication factor C (activator 1) 5, 36.5kDa;
STIL
SCL/TAL1 interrupting locus;
HLTF
helicase-like transcription factor; Methylation of
HLTF detected in serum is strongly correlated with
cell death in colorectal cancer6 and it is associated with
genesis and progression of colon, gastric and uterine
tumors7. HLTF is a common target for methylation and
epigenetic gene silencing in colon cancer and also is a
candidate colon cancer suppressor gene8.
TFF3
trefoil factor 3 (intestinal); The physiological role
of TFF3 in restoring the mucosa during neoadjuvant
chemoradiotherapy with fluoropyrimidines could be
interfered with treatment efficacy and
up-regulation of TFF3 after neoadjuvant
chemoradiotherapy is associated with a higher risk of
relapse9.
TTK
TTK protein kinase; TTK plays an important role in
proliferation and sorafenib resistance and act as
a potential therapeutic target for human hepatocellular
carcinoma.10.
VRK1
vaccinia related kinase 1;
APOBEC3B
apolipoprotein B mRNA editing enzyme, catalytic
polypeptide-like 3B;APOBEC3B is identified a
mutational signature; Up-regulation of APOBEC3B in
developing tumors drives cancer progression in breast
cancer11.
DLGAP5
discs, large (Drosophila) homolog-associated protein
5;
KIF14
kinesin family member 14;
FGFBP1
fibroblast growth factor binding protein 1;FGF-BP
releases immobilized FGFs and can function as an
angiogenic switch molecule in cancer. FGF-BP is
upregulated in early dysplastic lesions of the human
colon that are typically associated with a loss of
adenomatous polyposis coli and up-regulation of
β-catenin12.
AGR2
anterior gradient 2; AGR2 is an independent
prognostic factor in primary colorectal carcinoma13.
CAPN9
calpain 9;
ZWINT
ZW10 interacting kinetochore protein;
SLC35A3
solute carrier family 35 (UDP-N-acetylglucosamine
(UDP-GlcNAc) transporter), member A3;
GPR160
G protein-coupled receptor 160;
STXBP6
syntaxin binding protein 6 (amisyn);
DTL
denticleless E3 ubiquitin protein ligase homolog
Drosophila;
GALNT7
polypeptide N-acetylgalactosaminyltransferase 7;
GALNT7 was an oncogene. which inhibited the
proliferation, colony formation, migration, and
invasion of NPC-derived cells14.
BSPRY
B-box and SPRY domain containing;
HES6
hes family bHLH transcription factor 6;
C19orf33
chromosome 19 open reading frame 33;
CENPK
centromere protein K; Over-expression of this gene
is associated with poor prognoses and it can be used as
a novel tumor marker of ovarian cancer15.
PRR15L
proline rich 15-like;
E2F8
E2F transcription factor 8;
APOLD1
apolipoprotein L domain containing 1;
MND1
meiotic nuclear divisions 1 homolog (S. cerevisiae);
TMEM246
transmembrane protein 246;
SPIN4
spindlin family, member 4;
CDC42EP5
CDC42 effector protein (Rho GTPase binding) 5;
MANEAL
mannosidase, endo-alpha-like;
CMC1
C-x(9)-C motif containing 1;
PRR15
proline rich 15;
FAM221A
family with sequence similarity 221, member A;
CD24
CD24 molecule; CD24 was regulated by Wnt signaling
and confered enhanced colony forming ability and
enhanced cell motility-features16. The 5-FU-resistant
cells (n SGC7901 and SGC7901-FR) were also
enriched with cells expressing cluster of differentiation
(CD)133+, CD326+ and CD44+CD24-17.
HSPB1
heat shock 27kDa protein 1;
Phosphorylated HSPB1 might play an important role
in 5-FU resistance18.
ADIRF
adipogenesis regulatory factor;
PLA2G12B
phospholipase A2, group XIIB;
down-regulation
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