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.

Epi-Drugs in Heart Failure

“…Through the inhibition of DNMTs and HDACs, sulforaphane reduced methylation levels while enhancing Ac-H3 enrichment on the Nrf2 promoter. Epigenetic remodeling of the Nrf2 promoter may lead to sustained upregulation of the transcription factor with subsequent antioxidant effects on the failing heart ( 109 ).…”

Analyzing the Androgen Receptor Interactome in Prostate Cancer: Implications for Therapeutic Intervention

“…The appeal of targeting the action of these AR interactors has increased because some have been suggested to contribute to context-dependent transcription of AR target genes [40,41], and may thus differentially impact CaP progression. Moreover, a subset (e.g., p300, BRD4) possesses enzymatic properties that are relevant to AR function and are druggable [42,43]. However, these AR interactors are generally not AR-specific but also modulate the activity of other transcription factors.…”

The Epigenetic Regulation of Nonhistone Proteins by SETD7: New Targets in Cancer

“…ER and AR, ligand-dependent transcription factors, are activated by sex hormones and responsible for the regulation of cell proliferation, survival and differentiation ( Shafi et al, 2013 ; Berkel and Cacan, 2021 ) in breast ( Anestis et al, 2020 ) and prostate cancer ( Tan et al, 2015 ), respectively. As most transcription factors, activated ER or AR translocates into the nucleus and recruits other epigenetic enzymes, such as histone acetyltransferase or methyltransferase, to transactivate targeting genes expression ( Waddell et al, 2021 ). Unsurprisingly, aberrant expression ER and AR are risk factors in many cancers, including prostate, breast and lung cancers ( Burstein, 2020 ).…”