Estrogen receptor acetylation and phosphorylation in hormone responses

Abstract

In the USA, breast cancer accounts for approximately 30% of all cancers diagnosed and remains the second leading cause of cancer death in women. The importance of estrogen receptor alpha (ER␣) activity in breast cancer onset is evidenced by the efficacy of ER␣ antagonists for breast cancer prevention in highrisk individuals [1,2]. The Stathmin staging classification (TNM) includes ER␣ status [3], as the abundance of ER␣ determined by immunoreactivity provides independent evidence for high survival rate and lower relapse [4,5].Estrogens regulate cellular proliferation and differentiation of the normal breast. The two related nuclear receptors, ER␣ and ER␤, function as transcription factors (TFs) to regulate downstream target genes, co-ordinating cell-cycle progression within the mammary epithelial cell and contribute to intracrine and paracrine signaling. ERs are members of the nuclear steroid hormone receptor family, which function as ligand-dependent transcriptional regulators. The subcellular location of the ER␣ also contributes to distinct signaling pathways. Thus, in addition to the well-known nuclear function, membrane-associated ER␣ also functions through membrane tyrosine kinase receptor signaling pathways [6]. Additional types of functional ERs associated with plasma membranes, such as GPR30, are thought to regulate non-genomic signaling through second messenger Ca 2ϩ , nitric oxide and protein-lipid kinases [7]. The ER␣ encodes distinct functional domains (termed A-F) conserved with other members of the classical receptor subclass. The conserved DNA-binding domain consists of 68 amino acids with two zinc finger structures. The activation function (AF) domains, AF-1 and AF-2, of the ER␣ contribute synergistically to transcriptional induction. AF-1 function is induced by oncoproteins, growth factors, the co-activator p300, p68 RNA helicase A and several other signaling pathways [8][9][10] Abstract Histone acetylation is thought to facilitate binding of transcription factors (TFs) to specific target DNA sequences by destabilizing nucleosomes bound to the promoter region of a target gene. In addition, non-histone proteins including a subset of TFs and co-activators are acetylated by p300/CBP and P/CAF. The regulation of estrogen signaling by direct estrogen receptor alpha (ER␣) post-translational modification reveals a novel role for histone acetyltransferase in hormone signaling. ER␣ is acetylated and phosphorylated and phosphorylation occurs at multiple sites in response to kinase signaling. The finding that mutations with the ER␣ hinge domain lysine residues enhance hormone sensitivity suggests these residues may be involved in ligand-dependent transcriptional repression or transcriptional attenuation. Phosphorylation and acetylation of the ER regulates hormone signaling and is being assessed for a role in resistance to anti-estrogen therapy of ER␣-positive patients.

The emerging role of estrogen related receptorα in complications of non‑small cell lung cancers (Review)

“…The extent of ERREs within the ERR complexes of target genes is not known, but it is known to vary significantly based on the cell type, cellular proliferation state and differentiation and in response to organ specific stimuli (73), such as PPARα/sirtuin 1 (Sirt1) complex mediated ERR target suppression in the heart (78), and squamous metaplasia in the prostate gland (79) arising due to altered estrogen synthesis. The affinity of ERRα binding with ERREs is modulated by the extent of acetylation of four lysine residues in the Zn +2 finger and C-terminal extension of DBD, which is regulated by acetyltransferase P300/CBP-associated factor (PCAF) and deacetylases, histone deacetylase (HDAC8) and SIRT1 (79)(80)(81). This deacetylation mechanism is used by HDAC8 and SIRT1 cofactors to link the metabolic status with controlling ERRα target gene selection (80).…”

“…The affinity of ERRα binding with ERREs is modulated by the extent of acetylation of four lysine residues in the Zn +2 finger and C-terminal extension of DBD, which is regulated by acetyltransferase P300/CBP-associated factor (PCAF) and deacetylases, histone deacetylase (HDAC8) and SIRT1 (79)(80)(81). This deacetylation mechanism is used by HDAC8 and SIRT1 cofactors to link the metabolic status with controlling ERRα target gene selection (80).…”

Epigenetics and the Estrogen Receptor

“…BRCA1 binds the ERα to repress ligand‐induced gene expression. BRCA1 repression of ERα is opposed by endogenous cyclin D1 through physical association within local chromatin 45 (. 1).…”