Oncotarget

Research Papers:

Proximal and distal regulation of the HYAL1 gene cluster by the estrogen receptor α in breast cancer cells

Lydia Edjekouane, Samira Benhadjeba, Maïka Jangal, Hubert Fleury, Nicolas Gévry, Euridice Carmona and André Tremblay _

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Oncotarget. 2016; 7:77276-77290. https://doi.org/10.18632/oncotarget.12630

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Abstract

Lydia Edjekouane1,2, Samira Benhadjeba1,2, Maïka Jangal3, Hubert Fleury4, Nicolas Gévry3, Euridice Carmona4, André Tremblay1,2,5

1Research Center, CHU Sainte-Justine, Montréal, Québec, H3T 1C5 Canada

2Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada

3Department of Biology, Faculty of Sciences, University of Sherbrooke, Sherbrooke, Québec, J1K 2R1 Canada

4CHUM Research Center, Institut du cancer de Montréal, Montréal, Québec, H2X 0A9 Canada

5Department of Obstetrics & Gynecology, Faculty of Medicine, University of Montreal, Montréal, Québec, H3T 1J4 Canada

Correspondence to:

André Tremblay, email: [email protected]

Keywords: hyaluronidase, estrogen receptors, 3p21.3 cluster

Received: April 19, 2016    Accepted: September 24, 2016    Published: October 13, 2016

ABSTRACT

Chromosomal and genome abnormalities at the 3p21.3 locus are frequent events linked to epithelial cancers, including ovarian and breast cancers. Genes encoded in the 3p21.3 cluster include HYAL1, HYAL2 and HYAL3 members of hyaluronidases involved in the breakdown of hyaluronan, an abundant component of the vertebrate extracellular matrix. However, the transcriptional regulation of HYAL genes is poorly defined. Here, we identified the estrogen receptor ERα as a negative regulator of HYAL1 expression in breast cancer cells. Integrative data mining using METABRIC dataset revealed a significant inverse correlation between ERα and HYAL1 gene expression in human breast tumors. ChIP-Seq analysis identified several ERα binding sites within the 3p21.3 locus, supporting the role of estrogen as an upstream signal that diversely regulates the expression of 3p21.3 genes at both proximal and distal locations. Of these, HYAL1 was repressed by estrogen through ERα binding to a consensus estrogen response element (ERE) located in the proximal promoter of HYAL1 and flanked by an Sp1 binding site, required to achieve optimal estrogen repression. The repressive chromatin mark H3K27me3 was increased at the proximal HYAL1 ERE but not at other EREs contained in the cluster, providing a mechanism to selectively downregulate HYAL1. The HYAL1 repression was also specific to ERα and not to ERβ, whose expression did not correlate with HYAL1 in human breast tumors. This study identifies HYAL1 as an ERα target gene and provides a functional framework for the direct effect of estrogen on 3p21.3 genes in breast cancer cells.


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