Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression

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][1] . This article is highlighted in the In This Issue feature, [p. 331][2] [1]: /lookup/volpage/6/350?iss=4 [2]: /lookup/volpage/6/331?iss=4