Luminal lncRNAs Regulation by ERα-Controlled Enhancers in a Ligand-Independent Manner in Breast Cancer Cells.

Valentina Miano,Jamal Elhasnaoui,Michele De Bortoli,Giulia Basile,Eleonora Manitta,Valentina Rosti,Giulio Ferrero

doi:10.3390/ijms19020593

Valentina Miano, Jamal Elhasnaoui + Show 5 more

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https://doi.org/10.3390/ijms19020593

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Abstract

Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal BC phenotype. Recently, we demonstrated that even in absence of ligands ERα (apoERα) binds chromatin sites where it regulates transcription of several protein-coding and lncRNA genes. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts, thus representing a new signature of luminal BC genes. By the analysis of H3K27ac enrichment in hormone-deprived MCF-7 cells, we defined a set of Super Enhancers (SEs) occupied by apoERα, including one mapped in proximity of the DSCAM-AS1 lncRNA gene. This represents a paradigm of apoERα activity since its expression is largely unaffected by estrogenic treatment, despite the fact that E2 increases ERα binding on DSCAM-AS1 promoter. We validated the enrichment of apoERα, p300, GATA3, FoxM1 and CTCF at both DSCAM-AS1 TSS and at its associated SE by ChIP-qPCR. Furthermore, by analyzing MCF-7 ChIA-PET data and by 3C assays, we confirmed long range chromatin interaction between the SE and the DSCAM-AS1 TSS. Interestingly, CTCF and p300 binding showed an enrichment in hormone-depleted medium and in the presence of ERα, elucidating the dynamics of the estrogen-independent regulation of DSCAM-AS1 expression. The analysis of this lncRNA provides a paradigm of transcriptional regulation of a luminal specific apoERα regulated lncRNA.

Highlights

Estrogen Receptor α (ERα) is the key transcriptional factor of the luminal breast cancer subtype, which comprises three quarter of breast cancer cases [1], by mediating estrogen signaling in breast cancer cells
This therapy fails in one-fourth of ERα+ breast cancer cases because of de-novo or acquired endocrine resistance, which is generally characterized by accelerated tumor growth and increased aggressive behavior [5]
It has been reported that ERα binding to DSCAM-AS1 promoter is high in tumor tissues from patients unresponsive to Tamoxifen treatment and that DSCAM-AS1 expression is upregulated in Tamoxifen-resistant cellular models [22], contrary to typical estrogen-responsive genes that are strongly downregulated. These results suggest that distal putative enhancer or Super Enhancers (SEs) regions might be responsible for this peculiar transcriptional regulation and might be more generally involved in transcriptional regulation of cell-specific lncRNAs

Summary

Introduction

Estrogen Receptor α (ERα) is the key transcriptional factor of the luminal breast cancer subtype, which comprises three quarter of breast cancer cases [1], by mediating estrogen signaling in breast cancer cells. SERMs are synthetic compounds that function as agonists or antagonists for estrogen receptors in a tissue-specific manner. The first SERM that has been used successfully in the clinic is tamoxifen (TAM) which functions as cell type-specific anti-estrogens [3]. The most common endocrine treatments today are AIs, which block the biosynthesis of estrogens [4]. This therapy fails in one-fourth of ERα+ breast cancer cases because of de-novo or acquired endocrine resistance, which is generally characterized by accelerated tumor growth and increased aggressive behavior [5]

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