title: Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mitachi
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oike
authors.affiliation: Oncology Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Saito
authors.initials: S
authors.lastname: Higuchi
authors.affiliation: Oncology Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tominaga
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. tkkohno@ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D050882:CREB-Binding Protein / Q000172:deficiency*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D034622:RNA Interference; D000072020:Synthetic Lethal Mutations; D014158:Transcription, Genetic
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases