Data from Targeting p300 Addiction in <i>CBP</i>-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of <i>MYC</i> Expression

Abstract

<div>Abstract<p>Loss-of-function mutations in the <i>CBP/CREBBP</i> 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 <i>CBP</i>-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in <i>CBP</i>-deficient cancers identified the <i>CBP</i> paralog <i>p300/EP300</i>. Ablation of p300 in <i>CBP</i>-knockout and <i>CBP</i>-deficient cancer cells induced G<sub>1</sub>–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 <i>CBP</i>-deficient cells caused downregulation of <i>MYC</i> expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous <i>MYC</i> expression. The p300-HAT inhibitor C646 specifically suppressed the growth of <i>CBP</i>-deficient lung and hematopoietic cancer cells <i>in vitro</i> and <i>in vivo</i>; thus p300 is a promising therapeutic target for treatment of <i>CBP</i>-deficient cancers.</p><p><b>Significance:</b> 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 <i>CBP</i>-deficient cancers by inhibition of the p300 HAT activity. Patients with <i>CBP</i>-deficient cancers could benefit from therapy using p300-HAT inhibitors. <i>Cancer Discov; 6(4); 430–45. ©2015 AACR</i>.</p><p><i>See related commentary by Kadoch, p. 350</i>.</p><p>This article is highlighted in the In This Issue feature, p. 331</p></div>