CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers

Abstract

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s-1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to their ability to acetylate histone and non-histone proteins to modulate transcription. Work in the last 20 years has firmly established CBP/p300 as critical regulators for nuclear hormone signaling pathways, which drive tumor growth in several cancer types. Indeed, CBP/p300 are critical co-activators for the androgen receptor (AR) and estrogen receptor (ER) signaling in prostate and breast cancer, respectively. The AR and ER are stimulated by sex hormones and function as transcription factors to regulate genes involved in cell cycle progression, metabolism, and other cellular functions that contribute to oncogenesis. Recent structural studies of the AR/p300 and ER/p300 complexes have provided critical insights into the mechanism by which p300 interacts with and activates AR- and ER-mediated transcription. Breast and prostate cancer rank the first and forth respectively in cancer diagnoses worldwide and effective treatments are urgently needed. Recent efforts have identified specific and potent CBP/p300 inhibitors that target the acetyltransferase activity and the acetytllysine-binding bromodomain (BD) of CBP/p300. These compounds inhibit AR signaling and tumor growth in prostate cancer. CBP/p300 inhibitors may also be applicable for treating breast and other hormone-dependent cancers. Here we provide an in-depth account of the critical roles of CBP/p300 in regulating the AR and ER signaling pathways and discuss the potential of CBP/p300 inhibitors for treating prostate and breast cancer.

Keywords: CBP/p300; acetyltransferase; breast cancer; bromodomain; cancer epigenetics; histone acetylation; prostate cancer; transcription co-activator.

Figure 1

Structure and Function of acetyltransferases CBP/p300. (A) Structural modules of CBP/p300. Amino acid numbers are based on the p300 protein sequence. (B) Sites of histone acetylation catalyzed by CBP/p300 on the four core histones. All sites are regulated by CBP/p300; sites in red are downregulated by A-485 and sites in green are downregulated by both A-485 and GNE-049. (C) CBP/p300 function as co-activators of specific transcription factor. CBP/p300 inhibitors can reduce oncogene expression. Abbreviations: ac: acetylated lysine; Bromo: bromodomain; C/H1, C/H2 and C/H3: cysteine–histidine-rich regions 1, 2 and 3; NRID: the nuclear receptor interaction; HAT: histone acetyltransferase; IBiD: interferon-binding domain; KIX: a kinase-inducible CREB interaction region; NCBD: the nuclear co-activator-binding domain; SID/SRCID: steroid receptor co-activator protein-interaction domain; SRC: steroid receptor co-activator protein; TAZ: transcriptional adaptor zinc-binding domain; TF: transcription factor; ZZ: ZZ-type zinc finger.

Figure 2

Challenges in Hormone-Dependent Prostate and Breast Cancers. (A) An overview of the clinical challenges for hormone-dependent prostate cancer, luminal breast cancer, and LAR (luminal androgen receptor) triple-negative breast cancer. (B) Resistance to hormonal therapies is a critical clinical challenge after patients relapse on therapy, as depicted in the diagram.

Figure 3

Nuclear Hormone Receptor Signaling. (A) An overview of the androgen receptor signaling cascade and formation of the AR activation complex at the ARE in AR target genes. (B) An overview of the estrogen receptor signaling cascade and formation of the ER activation complex at the ERE in ER target genes. Ac: lysine acetylation; ARE: androgen response element; DHT: 5α-dihydrotestosterone; E2: 17β-Estradiol; ERE: estrogen response element; FKHD: forkhead motif; HSP: heat shock protein; T: testosterone.

Figure 4

Structure of Androgen and Estrogen Receptors and their Co-activator SRC-3. The structural domains of AR, ER and SRC-3 are shown. The sites of their interactions are depicted. The ligand-binding domain of the AR and ER where antagonists bind is indicated. AD: activation domain; AF: activation function; bHLH/PAS: basic helix-loop-helix/per-arnt-sim domain; CID: CBP/p300 interaction domain; DBD: DNA-binding domain; F: F domain in the C-terminus of nuclear receptors; HAT: histone acetyltransferase domain; LBD: ligand-binding domain; NTD: N-terminal domain; RID: receptor interaction domain; Q: polyglutamate region; ST: serine/threonine rich region.