Epigenetics and the Estrogen Receptor

Abstract

: The position effect variegation in Drosophila and Schizosaccharomyces pombe, and higher‐order chromatin structure regulation in yeast, is orchestrated by modifier genes of the Su(var) group, (e.g., histone deacetylases ([HDACs]), protein phosphatases) and enhancer E(Var) group (e.g., ATP [adenosine 5′‐triphosphate]‐dependent nucleosome remodeling proteins). Higher‐order chromatin structure is regulated in part by covalent modification of the N‐terminal histone tails of chromatin, and histone tails in turn serve as platforms for recruitment of signaling modules that include nonhistone proteins such as heterochromatin protein (HP1) and NuRD. Because the enzymes governing chromatin structure through covalent modifications of histones (acetylation, methylation, phosphorylation, ubiquitination) can also target nonhistone substrates, a mechanism is in place by which epigenetic regulatory processes can affect the function of these alternate substrates. The posttranslational modification of histones, through phosphorylation and acetylation at specific residues, alters chromatin structure in an orchestrated manner in response to specific signals and is considered the basis of a “histone code.” In an analogous manner, specific residues within transcription factors form a signaling module within the transcription factor to determine genetic target specificity and cellular fate. The architecture of these signaling cascades in transcription factors (SCITs) are poorly understood. The regulation of estrogen receptor (ERα) by enzymes that convey epigenetic signals is carefully orchestrated and is reviewed here.

The effect of low-dose experimental zearalenone intoxication on the immunoexpression of estrogen receptors in the ovaries of pre-pubertal bitches

“…The expression of ERs is inhibited by reversible methylation and acetylation of histones at the promoter (Leader et al 2006). Da Silva Faria et al (2008 reported morphological changes ("regression") in the ovaries, increased E 2 serum concentrations, and decreased mRNA expression of ovarian receptors ERα, ERβ1, and ERβ2 in the female offspring of rats suffering from protein-energy malnutrition.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Recent research has focused on mechanisms that regulate ERα expression in human breast cancer cells. Epigenetic mechanisms including DNA methylation and/or histone modifications are believed to contribute to silencing of ERα expression [129,130]. Several studies have demonstrated that ERα CpG islands are hypermethylated in ERα-negative human breast cancer cells and treatment of these cells with DNA methyltransferase inhibitors such as 5-azacitidine or decitabine elicits reexpression of functional ERα protein (Fig.…”

Circadian Clock and Breast Cancer: A Molecular Link

“…In addition, ERa appears to be directly acetylated by p300, which leads to a decrease in its transactivation activity. 23 Intriguingly, one of the lysines acetylated by p300, K303, is frequently mutated in early breast cancer lesions, 24 providing a direct link between HAT function and cancer development. Furthermore, mutation of K303 and subsequent ectopic expression of the mutated protein causes faster growth of cultured breast carcinoma cells.…”