Abstract

The estrogen receptor (ER) signaling regulates numerous physiological processes mainly through activation of gene transcription (genomic pathways). Caveolin1 (CAV1) is a membrane-resident protein that behaves as platform to enable different signaling molecules and receptors for membrane-initiated pathways.

CAV1 directly interacts with ERs and allows their localization on membrane with consequent activation of ER-non-genomic pathways. Loss of CAV1 function is a common feature of different types of cancers, including breast cancer. Two protein isoforms, CAV1α and CAV1β, derived from two alternative translation initiation sites, are commonly described for this gene.

However, the exact transcriptional regulation underlying CAV1 expression pattern is poorly elucidated. In this study, we dissect the molecular mechanism involved in selective expression of CAV1β isoform, induced by estrogens and downregulated in breast cancer.

Luciferase assays and Chromatin immunoprecipitation demonstrate that transcriptional activation is triggered by estrogen-responsive elements embedded in CAV1 intragenic regions and DNA-binding of estrogen-ER complexes.

This regulatory control is dynamically established by local chromatin changes, as proved by the occurrence of histone H3 methylation/demethylation events and association of modifier proteins as well as modification of H3 acetylation status.

Thus, we demonstrate for the first time, an estrogen-ERs-dependent regulatory circuit sustaining selective CAV1β expression.

Introduction

The estrogen receptor α and β (ERα, ER β) are members of the nuclear hormone receptor family, ligand-dependent transcription factors mediating signaling in estrogen-responsive cells.

 Activation of the ERα-dependent pathways is largely dependent on 17β-estradiol (E2), the most active circulating sex hormone that also binds to ERβ. E2/ER signaling exerts pleiotropic effects by multiple mechanisms.

These are in part established by direct binding to gene promoters harboring estrogen-responsive element/s (ERE) and recruitment of specific coregulator/s that activate transcriptional machinery through histones posttranslational modifications and/or epigenetic DNA configurations. […]

This is one of the scientific articles published by one or more synbrAIn collaborators and data scientists.

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