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• W2238488506 abstract "Abstract Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300. Ablation of p300 in CBP-knockout and CBP-deficient cancer cells induced G1–S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers. Significance: Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a “synthetic lethal–based therapeutic strategy” for CBP-deficient cancers by inhibition of the p300 HAT activity. Patients with CBP-deficient cancers could benefit from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430–45. ©2015 AACR. See related commentary by Kadoch, p. 350. This article is highlighted in the In This Issue feature, p. 331" @default.
• W2238488506 created "2016-06-24" @default.
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• W2238488506 date "2016-04-01" @default.
• W2238488506 modified "2023-10-10" @default.
• W2238488506 title "Targeting p300 Addiction in <i>CBP</i>-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of <i>MYC</i> Expression" @default.
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• W2238488506 doi "https://doi.org/10.1158/2159-8290.cd-15-0754" @default.
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