Pharmacological Inhibition of CBP/p300 Blocks Estrogen Receptor Alpha (ERα) Function through Suppressing Enhancer H3K27 Acetylation in Luminal Breast Cancer.

Autor: Waddell, Aaron, Mahmud, Iqbal, Ding, Haocheng, Huo, Zhiguang, Liao, Daiqing
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Zdroj: Cancers; Jun2021, Vol. 13 Issue 11, p2799, 1p
Abstrakt: Simple Summary: Breast cancer is the most common cancer in women, affecting 1 in 20 women globally. Breast cancer is divided into four subtypes: luminal A, luminal B, HER2-enriched, and basal-like. Estrogen receptor-positive breast cancer accounts for nearly 80% of all breast cancer cases and most breast cancer deaths occur in patients with breast cancer of luminal subtypes. Estrogen receptor antagonists are the standard-of-care treatment for this type of breast cancer; however, resistance to these treatments is common in the clinic. Therefore, we aimed to explore novel therapeutic strategies for inhibiting estrogen receptor activity in breast cancer. Estrogen receptor relies on two highly related proteins, known as CBP and p300, to function. We report that CBP/p300 inhibitors effectively block estrogen receptor function and inhibit breast cancer cell growth. These findings reveal CBP and p300 as promising new targets for breast cancer treatment. Estrogen receptor alpha (ER) is the oncogenic driver for ER+ breast cancer (BC). ER antagonists are the standard-of-care treatment for ER+ BC; however, primary and acquired resistance to these agents is common. CBP and p300 are critical ER co-activators and their acetyltransferase (KAT) domain and acetyl-lysine binding bromodomain (BD) represent tractable drug targets, but whether CBP/p300 inhibitors can effectively suppress ER signaling remains unclear. We report that the CBP/p300 KAT inhibitor A-485 and the BD inhibitor GNE-049 downregulate ER, attenuate estrogen-induced c-Myc and Cyclin D1 expression, and inhibit growth of ER+ BC cells through inducing senescence. Microarray and RNA-seq analysis demonstrates that A-485 or EP300 (encoding p300) knockdown globally inhibits expression of estrogen-regulated genes, confirming that ER inhibition is an on-target effect of A-485. Using ChIP-seq, we report that A-485 suppresses H3K27 acetylation in the enhancers of ER target genes (including MYC and CCND1) and this correlates with their decreased expression, providing a mechanism underlying how CBP/p300 inhibition downregulates ER gene network. Together, our results provide a preclinical proof-of-concept that CBP/p300 represent promising therapeutic targets in ER+ BC for inhibiting ER signaling. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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