Tanget al., Science 376 , eabe1505 (2022) 27 May 2022 11 of 13
G
F
FOSL1 OETAZ^
OE
TAZ/FO
SL1 OEYAP OE
YAP/FOSL1
OE
-20%
0%
20%
40%
60%
80%
100%
% of chromatin accessibility change
compared to control
***
***
***
***
***
***
Chromatin accessibility change
compared to control
CRPC-AR peaks
CRPC-SCL peaks
log10 verteporfin (uM)
Percent of control viability
35hr verteporfin titration
-1 0 1
0
50
100
150
log10 T-5224 (uM)
48 hr T-5224 titration
12
0
50
100
150
Percent of control viability
MSKPCa2
MSKPCa3
MSKPCa2
MSKPCa3
A
D
B
CRPC-SCL peaks CRPC-AR peaks
E
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Enrichment score (ES)
FOSL1 OE TAZ/FOSL1 OE YAP/FOSL1 OE
CRPC-SCL
NES = 2.63
FDR = 0.00
CRPC-SCL
NES = 2.23
FDR = 0.00
CRPC-SCL
NES = 2.46
FDR = 0.00
GSEA of LNCaP upon overexpression
Chromatin accessibility of LNCaP upon overexpression
-2.0Peak center2.0Kb
0.0
0.1
0.2
0.3
Coverage on peaks (bpm)
-2.0 Peak center2.0Kb-2.0Peak center2.0Kb-2.0 Peak center2.0Kb-2.0Peak center2.0Kb-2.0 Peak center2.0Kb
-2.0Peak center2.0Kb-2.0 Peak center2.0Kb-2.0Peak center2.0Kb-2.0 Peak center2.0Kb-2.0Peak center2.0Kb-2.0 Peak center2.0Kb
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
CRPC-AR peaks
CRPC-SCL peaks
Control FOSL1 OE TAZ OE TAZ/FOSL1 OE YAP OE YAP/FOSL1 OE
Coverage on
peaks (bpm)
C
YAP/TAZ activity in SU2C YAP/TAZ activity in WCM
AR expression (log2(FPKM+1))
YAP
/TAZ
activity scores
Fig. 7. Evidence of the role of AP-1, YAP, and TAZ in CRPC-SCL from
overexpression, small-molecule inhibition, and patient transcriptome
findings.(A) Chromatin accessibility changes uponFOSL1, TAZ/FOSL1,
TAZ, YAP/FOSL1,andYAPoverexpression in LNCaP cells at CRPC-AR and
CRPC-SCL peaks. (B) Average percentage of chromatin accessibility changes
uponFOSL1, TAZ/FOSL1, TAZ, YAP/FOSL1,andYAPoverexpression in
LNCaP compared to control at CRPC-AR and CRPC-SCL peaks. ***P <0.001
(permutation test). (C) Overexpression ofFOSL1in LNCaP cells shows
up-regulation of CRPC-SCL signature genes. (D) Effect of verteporfin on
MSKPCa2 (CRPC-AR) and MSKPCa3 (CRPC-SCL) cell growth. (E) Effect
of T-5224 on MSKPCa2 and MSKPCa3 cell growth. (F) YAP/TAZ activity (sum
of z-scores) is significantly higher in CRPC-SCL patients. ****P <0.0001,
**P < 0.01 (one-tailed Wilcoxon rank-sum test, CRPC-SCL compared
to the other groups). (G) YAP/TAZ activity is negatively correlated with
AR expression across the 266 SU2C patients with Corr =–0.201 and
P <0.001.
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