Exploitation of EP300 and CREBBP Lysine Acetyltransferases by Cancer

Abstract

p300 and CREB-binding protein (CBP), two homologous lysine acetyltransferases in metazoans, have a myriad of cellular functions. They exert their influence mainly through their roles as transcriptional regulators but also via nontranscriptional effects inside and outside of the nucleus on processes such as DNA replication and metabolism. The versatility of p300/CBP as molecular tools has led to their exploitation by viral oncogenes for cellular transformation and by cancer cells to achieve and maintain an oncogenic phenotype. How cancer cells use p300/CBP in their favor varies depending on the cellular context and is evident by the growing list of loss- and gain-of-function genetic alterations in p300 and CBP in solid tumors and hematological malignancies. Here, we discuss the biological functions of p300/CBP and how disruption of these functions by mutations and alterations in expression or subcellular localization contributes to the cancer phenotype.

Figure 1.

p300/CREB-binding protein (CBP) regulate the cell cycle at multiple points. The diagram summarizes the known functions of p300/CBP at different points along the cell cycle. The E2F family of transcription factors uses p300/CBP as transcriptional coactivators to facilitate expression of E2F target genes that orchestrate the transition from G₁ to S. p300 also facilitates S phase progression by acetylating the DNA replication machinery (e.g., FEN1 and Dna2) and the histones surrounding the replication origins (e.g., H3K18). CBP promotes progression through mitosis by regulating the function of the anaphase-promoting complex (APC)/C complex.

Figure 2.

Frequency of the different types of mutations in p300 and CBP in cancer. The majority of genetic lesions to p300 or CBP in cancer are missense mutations followed by nonsense mutations, deletions, and a small number of insertions.

Figure 3.

The acetyltransferase domains of p300 and CBP are hotspots for mutations in cancer. (A) The number of tumors of different origins with missense mutations along the p300 and CBP proteins domain structures is shown (Forbes et al. 2015). CH1, Cysteine/histidine-rich region 1; BR, bromodomain; PHD, plant homeodomain finger; RING, Really Interesting New Gene finger domain; KAT, lysine acetyltransferase domain; CH3, cysteine/histidine-rich region 3 (also referred to as TAZ2); IBiD, IRF3-binding domain. (B) The residues in the KAT domains of p300 and CBP that are frequently mutated in cancer are indicated. Residues in red are important for the KAT activity. The four most common residues mutated in p300 reside close to the acetyl-CoA-binding site as indicated in the crystal structure (Liu et al. 2008; Maksimoska et al. 2014).