Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression
Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression
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DOI：
10.1158/2159-8290.cd-15-0754
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发表时间：
2016-04-01
期刊：
影响因子：
28.2
通讯作者：
Kohno, Takashi
中科院分区：
文献类型：
--
作者：
Ogiwara, Hideaki;Sasaki, Mariko;Kohno, Takashi
编码组蛋白乙酰转移酶(HAT)的CBP/CREBBP基因功能缺失突变存在于多种人类肿瘤中，包括肺癌、膀胱癌、胃癌和造血癌。因此，开发一种能够特异性杀伤CBP缺陷的癌细胞的分子靶向方法将极大地提高癌症治疗水平。对CBP缺陷癌症中合成致死基因的功能筛选确定了CBP paralog p300/EP300。在CBP基因敲除和CBP缺陷的癌细胞中，p300的消融诱导G(1)-S细胞周期停滞，随后发生细胞凋亡。全基因组基因表达分析表明，MYC是导致合成致死性的主要因素。事实上，在CBP缺乏的细胞中，p300的消融通过减少其启动子中的组蛋白乙酰化而导致MYC表达的下调，而这种致命性可以通过外源MYC的表达来挽救。P300-HAT抑制剂C646在体内外特异性地抑制CBP缺陷的肺和造血癌细胞的生长，因此p300是治疗CBP缺陷的癌症的一个有前途的治疗靶点。在这里，我们提出了一种通过抑制p300 HAT活性来治疗CBP缺陷型癌症的“基于合成致死的治疗策略”。CBP缺陷的癌症患者可以从使用p300-HAT抑制剂的治疗中受益。(C)2015年AACR。
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 G(1)-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 down-regulation 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. (C) 2015 AACR.