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

Cancer Discov. 2016 Apr;6(4):430-45. doi: 10.1158/2159-8290.CD-15-0754. Epub 2015 Nov 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • CREB-Binding Protein / deficiency*
  • Cell Line, Tumor
  • Chromatin Assembly and Disassembly
  • Disease Models, Animal
  • E1A-Associated p300 Protein / antagonists & inhibitors
  • E1A-Associated p300 Protein / genetics*
  • E1A-Associated p300 Protein / metabolism
  • G1 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Neoplastic
  • Heterografts
  • Histone Acetyltransferases / antagonists & inhibitors
  • Humans
  • Mice
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Proto-Oncogene Proteins c-myc / genetics*
  • RNA Interference
  • Synthetic Lethal Mutations*
  • Transcription, Genetic


  • Proto-Oncogene Proteins c-myc
  • CREB-Binding Protein
  • E1A-Associated p300 Protein
  • Histone Acetyltransferases