Post-Transcriptional and Epigenetic Regulation of Estrogen Signaling

Abstract

Post-translational and epigenetic regulation are important mechanisms controlling functions of genes and proteins. Although the "classic" estrogen receptors (ERs) have been acknowledged to function in mediating estrogen effects via transcriptional mechanisms, estrogenic agents modulate the turnover of several proteins via post-transcriptional and post-translational pathways including epigenetics. For instance, the metabolic and angiogenic action of G-protein coupled estrogen receptor (GPER) in vascular endothelial cells has been recently elucidated. By interacting with GPER, 17β-estradiol (E2) and the GPER agonist G1 enhance endothelial stability of 6phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and capillary tube formation by increasing ubiquitin specific peptidase 19 (USP19) levels, thereby reducing PFKFB3 ubiquitination and proteasomal degradation. In addition to ligands, the functional expression and trafficking of ERs can be modulated by post-translational modification, including palmitoylation. MicroRNAs (miRNAs), the most abundant form of endogenous small RNAs in humans, regulate multiple target genes and are at the center of the multi-target regulatory network. This review discusses also the emerging evidence how miRNAs affect glycolytic metabolism in cancer, as well as their regulation by estrogens. Restoring dysregulated miRNA expression represents a promising strategy to counteract the progression of cancer and other disease conditions. Accordingly, estrogen posttranscriptional regulatory and epigenetic mechanisms represent novel targets for pharmacological and non-pharmacological intervention for the treatment and prevention of hormone-sensentive non-communicable diseases, including estrogen-sensitive cancers of the reproductive system in women.

Sex Differences in Colon Cancer: Genomic and Nongenomic Signalling of Oestrogen

“…Oestrogen has been implicated in promoting angiogenesis, the formation of new blood vessels, which is essential for tumour growth and metastasis [69] and can upregulate the expression of vascular endothelial growth factor (VEGF), a key factor involved in angiogenesis [70]. Oestrogen may also influence epigenetic modifications in colon cancer cells [71] to effect post-translational DNA methylation patterns, histone modifications, and chromatin remodelling, potentially impacting gene expression and cellular behaviour [72]. Nuclear oestrogen receptors may also play a role in inducing or influencing the process of epithelial-mesenchymal transition (EMT) [73], which is involved in tumour metastases in colon cancer [74].…”