MYC is a key determinant of cancer cell survival under p300- or CBP-depletion in CBP-KO or p300-KO cells, respectively. MYC is a key determinant of cancer cell survival under p300- or CBP-depletion in CBP-KO or p300-KO cells, respectively. A, genome-wide gene expression analysis identified MYC as the gene most strongly associated with the observed synthetic lethality. A Benn analysis identified 1,936 genes that exhibited significant changes in expression specifically upon p300 depletion in H1299 CBP-KO cells and CBP depletion in H1299 p300-KO cells. WikiPathways database analysis identified the 13 top pathways (P < 0.001) comprising these 1,936 genes. MYC was identified as the gene most commonly included in the 13 pathways. B and C, expression profiles of H1299 CBP/p300 WT and CBP-KO or p300-KO cells following p300 depletion. H1299 CBP/p300 WT, CBP-KO, and p300-KO cells were transfected with siNT, sip300 (D1), or siCBP (D2). After 48 hours, the cells were harvested and subjected to quantitative RT-PCR analysis and immunoblot analysis. The relative changes in gene expression relative to siNT are shown (B). Data, means ± SD. Immunoblot analysis of p300, CBP, MYC, and β-actin (loading control) (C). D, suppression of proliferation of H1299 CBP-KO cells by p300 depletion was rescued by exogenous expression of WT p300, but not HAT-defective p300. H1299 CBP-KO cells were transfected with a plasmid expressing p300 or HAT-defective p300 (HAT-) cDNAs. Twenty-four hours after transfection, the cells were further transfected with sip300 (3′UTR: targeting the 3′ UTR region of the p300 mRNA) or siNT. Forty-eight hours later (day 0), cells were seeded in 96-well plates. Cell viability was measured at 5 days. Immunoblot analyses of p300, MYC, and β-actin (loading control). Data, means ± SD. E, suppression of proliferation of H1299 CBP-KO cells by p300 depletion rescued by exogenous expression of MYC, but not CCND1 and CDC45. H1299 CBP-KO cells with or without stable exogenous MYC, CCND1, or CDC45 cDNA expression were transfected with siNT or sip300 (D1). Forty-eight hours later (day 0), cells were seeded in 96-well plates. Cell viability was measured at 5 days. Immunoblot analyses of p300, MYC, CCND1, CDC45, and β-actin (loading control) at 48 hours are shown. Data, means ± SD. Vec, vector. Hideaki Ogiwara et al. Cancer Discov 2016;6:430-445 ©2016 by American Association for Cancer Research