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

Abstract

Simple Summary

The CREB-binding protein (CBP) and p300 are paralogous lysine acetyltransferases that serve as critical co-activators for transcription factors involved in diverse signaling pathways in cancer. Work in the last two decades has firmly established CBP and p300 as important regulators of nuclear hormone signaling mediated by nuclear receptors, such as the androgen receptor (AR) and estrogen receptor (ER). The AR and ER promote tumor growth in hormone-dependent prostate and breast cancer, respectively. Inhibitors of androgen and estrogen signaling are the standard-of-care therapeutics for treating these cancers. However, resistance to current therapies remains a significant clinical problem. Inhibition of CBP and p300 as a means to block the transactivation activity of the AR and ER is an emerging therapeutic strategy for prostate and breast cancers. This review describes how CBP and p300 regulate androgen and estrogen signaling and discusses therapeutic potential of newly discovered potent CBP/p300 inhibitors for treating prostate and breast cancer.

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.