Fig. 1: Simultaneous inhibition of CBP/p300 causes synthetic lethality in SMARCB1-deficient cancer cells.

a Immunoblot analysis of SMARCB1 and β-actin expression in JMU-RTK-2 + SMARCB1 and JMU-RTK-2 -SMARCB1 cells. The experiments were repeated twice independently with similar results. b Heatmap showing the viability of HEK293T, JMU-RTK-2 + SMARCB1, and JMU-RTK-2 -SMARCB1 cells transfected with siRNAs targeting 30 paralog pairs. Cells were transfected for 48 h with the indicated siRNAs. The cells were then reseeded and transfected repeatedly with the indicated siRNAs for 48 h. The cells were then reseeded and incubated for 7 days. Cell viability is shown as a heatmap. c Heatmap showing the viability of SMARCB1-proficient (786-O and H460) and SMARCB1-deficient (G402 and HS-ES-2R) cell lines transfected with the indicated paralog pairs of siRNAs. Cells were transfected for 48 h with the indicated siRNAs. The cells were then reseeded and transfected repeatedly with the indicated siRNAs for 48 h. The cells were then reseeded and incubated for 7 days. Cell viability is shown as a heatmap. d Immunoblot analysis of SMARCB1, CBP, p300, β-actin, and histone H3 and H3K27ac expression in SMARCB1-proficient and SMARCB1-deficient cell lines. e Viability of SMARCB1-proficient (786-O, VMRC-RCZ, 786-O, ES2, H460, and H2228) and SMARCB1-deficient (NEPS, G402, JMU-RKT-2, HS-ES-2R, G401, and HS-ES-1) cell lines transfected with siRNAs specific for CREBBP + EP300, or with NT (non-targeting) siRNA. Cells were transfected for 48 h with the indicated siRNAs. The cells were then reseeded and transfected repeatedly with the indicated siRNAs for 48 h. The cells were then reseeded and incubated for 7 days. Data are presented as the mean ± SEM (standard error of the mean), n = 3 independent experiments. f Viability of JMU-RTK-2 +SMARCB1 and JMU-RTK-2 -SMARCB1 cells transfected with siRNAs specific for CREBBP and/or EP300, or with NT siRNA. Cells were transfected for 48 h with the indicated siRNAs. The cells were then reseeded and transfected repeatedly with the indicated siRNAs for 48 h. The cells were then reseeded and incubated for 7 days. Data are presented as the mean ± SEM, n = 3 independent experiments. g Viability of SMARCB1-proficient (786-O and VMRC-RCZ) and SMARCB1-deficient (HS-ES-1, NEPS, G402, and HS-ES-2R) cell lines transfected with siRNAs specific for CREBBP and/or EP300, or with NT siRNA. Cells were transfected for 48 h with the indicated siRNAs. The cells were then reseeded and transfected repeatedly with the indicated siRNAs for 48 h. The cells were then reseeded and incubated for 7 days. Data are presented as the mean ± SEM, n = 3 independent experiments. h Chemical structures of CBP/p300 dual inhibitors A-485, inobrodib, and CP-C27. i Histone acetylation (HAT) activity of CBP and p300 in vitro. The IC₅₀ (50% inhibitory concentration) values denoting the inhibitory effects of CP-C27 are shown. Data are presented as the mean ± SD (standard deviation), n = 2 independent experiments. j IC₅₀ values of the CBP/p300 inhibitors CP-C27, A-485, and inobrodib, the EZH2 inhibitor tazemetostat, and the EZH1/EZH2 inhibitor valemetostat in HEK293T, JMU-RTK-2 +SMARCB1, and JMU-RTK-2 -SMARCB1 cells. Cells were treated with inhibitors for 6 days and IC₅₀ values were calculated based on cell viability. Data are presented as the mean ± SEM, n = 3 independent experiments. k–m IC₅₀ values for CBP/p300 inhibitors CP-C27 (k), A-485 (l), and inobrodib (m) in SMARCB1-proficient (H460, H1048, H2009, H2228, 786-O, H358, Caki-1, HEK293T, VMRC-RCZ, and ES2) and SMARCB1-deficient (HS-ES-2M, HS-ES-2R, A-204, NEPS, G401, G402, HS-ES-1, and JMU-RTK-2) cells (corresponding to Supplementary Fig. 1o–q). Cells were treated with inhibitors for 6 days and IC₅₀ values were calculated based on cell viability. Data are presented as the mean ± SEM, (SMARCB1+ ; n = 10 biological independent cell lines, SMARCB1-; n = 8 biological independent cell lines). For all experiments, p-values were determined by an unpaired two-tailed Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001.