An epigenetic mechanism linking diethylstilbestrol to breast cancer
2014 Study Highlights
- EZH2 is a histone methylase specific to histone 3 lysine 27, which is associated with breast cancer.
- EZH2 expression is induced by estradiol (E2) in vitro and in vivo.
- EZH2 expression is also induced by EDCs (BPA and DES).
- ERs coordinate with MLLs during E2/BPA/DES-induced EZH2 expression.
- Mechanistic insight of EZH2 gene regulation and its endocrine disruption.
Enhancer of Zeste homolog 2 (EZH2), a methyltransferase specific to histone 3 lysine 27, is a critical player in gene silencing and is overexpressed in breast cancer.
Our studies demonstrate that EZH2 is transcriptionally induced by estradiol in cultured breast cancer cells and in the mammary glands of ovariectomized rats.
EZH2 promoter contains multiple functional estrogen-response elements. Estrogen receptors (ERs) and ER coregulators such as mixed lineage leukemia (MLL) histone methylases (MLL2 and MLL3) and histone acetyltransferase CBP/P300 bind to the EZH2 promoter in the presence of estradiol and regulate estradiol-induced EZH2 expression. EZH2 expression is also increased upon exposure to estrogenic endocrine disrupting chemicals (EDCs) such as bisphenol-A (BPA) and diethylstilbestrol (DES). Similar to estradiol, BPA and DES-induced EZH2 expression is coordinated by ERs, MLLs and CBP/P300.
In summary, we demonstrate that EZH2 is transcriptionally regulated by estradiol in vitro and in vivo, and its expression is potentially dysregulated upon exposure to estrogenic EDCs.
Sources and more information
- Histone Methyltransferase EZH2 Is Transcriptionally Induced by Estradiol as Well as Estrogenic Endocrine Disruptors Bisphenol-A and Diethylstilbestrol, Journal of Molecular Biology, Volume 426, Issue 20, Pages 3426–3441, doi.org/10.1016/j.jmb.2014.07.025, 9 October 2014.