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

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

doi:10.18632/oncotarget.12630

Lydia Edjekouane, Euridice Carmona + Show 5 more

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https://doi.org/10.18632/oncotarget.12630

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Journal: Oncotarget	Publication Date: Oct 13, 2016
Citations: 13	License type: cc-by

Affiliation: Université de Sherbrooke, Université de Montréal

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.

Highlights

Mammalian hyaluronidases are involved in the hydrolysis of the glycosaminoglycan hyaluronan, a critical component of the extracellular matrix that regulates cell growth, migration, and differentiation, and other processes such as extracellular water and protein homeostasis, cartilage and vascular integrity
We report a distinct and selective response to estrogen among the 3p21.3 locus genes in breast cancer cells, where the HYAL1 gene was repressed as compared to HYAL2 and HYAL3, and to other genes tested within the cluster
This negative regulation of HYAL1 by ERα provides a mechanism supporting the specific inverse correlation we found between ESR1 and HYAL1, but not with HYAL2 or HYAL3 in the METABRIC cohort consisting of 1980 cases of breast cancer

Summary

Introduction

Mammalian hyaluronidases are involved in the hydrolysis of the glycosaminoglycan hyaluronan, a critical component of the extracellular matrix that regulates cell growth, migration, and differentiation, and other processes such as extracellular water and protein homeostasis, cartilage and vascular integrity. Allelic imbalance of the HYAL1/2/3 clustered genes was reported in tumor and stroma tissues, and in particular, HYAL1 expression was significantly reduced in serous epithelial ovarian cancer compared to normal ovaries or to other ovarian cancer subtypes [10, 16, 17]. Consistent with such HYAL1 reduction, extracellular accumulation of hyaluronan is often observed in ovarian tumor stroma and pericellular matrix with correlation to poor disease outcome [3, 18]

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