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.
Highlights
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 [1]
Since Caveolin1 plays a critical role in breast cancer, and its down regulation increases tumor aggressiveness [31], we first explore the profiles of CAV1 mRNA variants in breast cell lines, like MCF7, that are ERα++ HER2-/+ cancer cells; MCF10A, that are triple negative normal cells; MDA231, that are triple negative cancer cells and in human breast tumors samples negative for ERα according to Subik K. et al 2010 [36]
CAV1 protein is present in two main isoforms, namely CAV1α and CAV1β, of which the β variant lacks a region of 31 amino acids present at NH2-terminal of CAV1α [37], CAV1 gene presents two major transcription starts (Start 1 and 2) originating the longer transcripts CAV1α (NM_001753.5) or CAV1β (NM_001172895.1) by alternative splicing and the shorter one CAV1β (NM_001172896.2, ENST00000393468.1) (Figure 1a)
Summary
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 [1]. E2/ER signaling exerts pleiotropic effects by multiple mechanisms [2,3] 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 [4,5,6]. Besides their role in gene expression regulation, ERs trigger non-genomic pathways initiated at membrane level through direct interaction with Caveolin (CAV1), the main structural protein of caveolae microdomains [7,8,9,10]. Most of human breast tumors are ERα positive and anti-ER hormonal therapy represents the major therapeutic approach [18,19,20], the treatment of triple-negative breast cancers remains a challenge and still lacks a definite cure [19,20,21,22]
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