Science - USA (2022-05-27)

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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