Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

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 specifi cally killing CBP-defi cient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP -defi cient cancers identifi ed the CBP paralog p300/EP300 . Ablation of p300 in CBP -knockout and CBP -defi cient 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 -defi cient 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 specifi cally suppressed the growth of CBP -defi cient lung and hematopoietic cancer cells in vitro and in vivo ; thus p300 is a promising therapeutic target for treatment of CBP -defi cient 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 lethalbased therapeutic strategy" for CBP -defi cient cancers by inhibition of the p300 HAT activity. Patients with CBP -defi cient cancers could benefi t from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430-45.

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

“…This property is essential as the mitigation of carcinogenic risks associated with p53 inhibition requires that the mode of action be temporary and reversible. Although previous studies by Rhoda M. Alani's (32) and Takashi Kohno's (40) groups demonstrated the cancer-killing properties of C646 at 10 and 15 mmol/L respectively, we discovered that a low dose of 1 mmol/L C646 could protect normal cells from p53-dependent apoptosis. This suggests that the dose of C646 may affect the types of substrates regulated by p300/CBP, resulting in contextual functional effects.…”

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

“…These include ARID1A and ARID1B (56), SMARCA2 and SMARCA4 (57), and most recently CBP and EP300 (58). Although the roles of these genes in tumorigenesis are similarly unclear, these examples of synthetic lethality can now be expanded to include UBB, a ubiquitin-encoding gene that serves as a biomarker for a clinically aggressive HGSOC subtype, and its paralog UBC.…”

BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion

“…As a result, specifically disrupting the ERG-BRD4 interaction with BET inhibitors may serve an equally important, yet disparate purpose to prevent PCa progression, in addition to disrupting the AR-BRD4 interaction and AR-mediated expression of TMPRSS2-ERG fusions. In combination with other therapies such as protein acetyltransferase inhibitors including I-CBP112 and C646 [49, 50] or therapies targeting other key PCa mutations, disruption of the ERG-BRD4 interaction may prove highly effective for a subset of advanced PCa.…”