Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells

Abstract

In mammals, molecular mechanisms and factors involved in the tight regulation of telomerase expression and activity are still largely undefined. In this study, we provide evidence for a role of estrogens and their receptors in the transcriptional regulation of hTERT, the catalytic subunit of human telomerase and, consequently, in the activation of the enzyme. Through a computer analysis of the hTERT 5′-flanking sequences, we identified a putative estrogen response element (ERE) which was capable of binding in vitro human estrogen receptor α (ERα). In vivo DNA footprinting revealed specific modifications of the ERE region in ERα-positive but not ERα-negative cells upon treatment with 17β-estradiol (E2), indicative of estrogen-dependent chromatin remodelling. In the presence of E2, transient expression of ERα but not ERβ remarkably increased hTERT promoter activity, and mutation of the ERE significantly reduced this effect. No telomerase activity was detected in human ovary epithelial cells grown in the absence of E2, but the addition of the hormone induced the enzyme within 3 h of treatment. The expression of hTERT mRNA and protein was induced in parallel with enzymatic activity. This prompt estrogen modulation of telomerase activity substantiates estrogen-dependent transcriptional regulation of the hTERT gene. The identification of hTERT as a target of estrogens represents a novel finding which advances the understanding of telomerase regulation in hormone-dependent cells and has implications for a potential role of hormones in their senescence and malignant conversion.

ACKNOWLEDGMENTS

We are grateful to Jan-Ake Gustafsson for the ERβ expression vector and to Maria Blasco for antibody K-370. We also thank the anonymous reviewer for very helpful suggestions on the role of c-myc in the response of telomerase to estrogens.

This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero della Sanità, Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST), and the National Cancer Institute of Canada (NCIC) to S.B.

S.M. and S.N. contributed equally to this work.