Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents

Abstract

The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.

Keywords: CBP/p300; cancer therapy; gene transcription; small molecule inhibitors; tumorigenesis.

Figure 1

Modulation of CBP/p300-induced histone acetylation by histone reader, histone modification proteins and the ubiquitin hydrolase USP24. A. CBP/p300 proteins consist of nuclear receptor interaction domain (NRID), transcriptional-adaptor zinc-finger domain 1 (TAZ1, also known as CH1), kinase inducible domain of CREB interacting domain (KIX), bromodomain (Bromo), PHD finger, histone acetyltransferase domain (HAT) including the autoinhibitory loop (AIL), ZZ-type zinc finger domain (ZZ), TAZ2 and interferon-binding domain (IBiD). B. CBP/p300 interact with BRD4 to induce H3K27ac, and BRG1 is then recruited to acetylated histone sites to enhance H3K27ac and gene transcription. P300 also forms a complex with UTX and MLL4, driving H3K4 mono-methylation (Me1) which further augments H3K27ac and transcriptional activation. In addition, SMARCB1 and other SWI/SNF subunit proteins recruit p300 to distal enhancers, rather than promoters, to induce H3K27ac and gene transcription. C. USP24 decreases p300 protein ubiquitination and proteasome-mediated degradation, thereby increasing p300 protein expression and H3K27ac.

Figure 2

The CBP/p300 and BET bromodomain dual inhibitor NEO2734 suppresses H3K27 acetylation and oncogene transcription and expression. CBP/p300 induce H3K27 acetylation and recruit the BET bromodomain protein BRD4 at oncogene promoters, typical enhancers and super-enhancers, leading to oncogene transcriptional activation and over-expression. Treatment with NEO2734 blocks H3K27 acetylation and displaces BRD4 at oncogene promoters, typical enhancers and super-enhancers, leading to oncogene transcriptional suppression.