論文 - 詳細
| RRC ID | 64933 |
|---|---|
| 著者 | Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S, Tominaga Y, Kohno T. |
| タイトル | Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression. |
| ジャーナル | Cancer Discov |
| Abstract |
UNLABELLED: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. |
| 巻・号 | 6(4) |
| ページ | 430-45 |
| 公開日 | 2016-4-1 |
| DOI | 10.1158/2159-8290.CD-15-0754 |
| PII | 2159-8290.CD-15-0754 |
| PMID | 26603525 |
| MeSH | 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 |
| IF | 29.497 |
| リソース情報 | |
| ヒト・動物細胞 | TE-8(RCB2098) TE-10(RCB2099) |