miR-22 Inhibits Estrogen Signaling by Directly Targeting the Estrogen Receptor α mRNA

Abstract

Estrogen receptor α (ERα) is a ligand-regulated transcription factor with a broad range of physiological functions and one of the most important classifiers in breast cancer. MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as important regulators of gene expression in a plethora of physiological and pathological processes. Upon binding the 3′ untranslated region (UTR) of target mRNAs, miRNAs typically reduce their stability and/or translation. The ERα mRNA has a long 3′ UTR of about 4.3 kb which has been reported to reduce mRNA stability and which bears evolutionarily conserved miRNA target sites, suggesting that it might be regulated by miRNAs. We have performed a comprehensive and systematic assessment of the regulatory role of all miRNAs that are predicted to target the 3′ UTR of the ERα mRNA. We found that miR-22 represses ERα expression most strongly and by directly targeting the ERα mRNA 3′ UTR. Of the three predicted miR-22 target sites in the 3′ UTR, the evolutionarily conserved one is the primary target. miR-22 overexpression leads to a reduction of ERα levels, at least in part by inducing mRNA degradation, and compromises estrogen signaling, as exemplified by its inhibitory impact on the ERα-dependent proliferation of breast cancer cells.

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miR-22 Inhibits Estrogen Signaling by Directly Targeting the Estrogen Receptor α mRNA

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We are grateful to F. Gannon and D. Trono for gifts of reagents. We thank Peter Dudek, Julian Pakay, Asvin Lakkaraju, and Jurgi Camblong for critical reading of the manuscript. We are indebted to the team of the genomics platform of the NCCR Frontiers-in-Genetics at the University of Geneva for help with miRNA expression profiling and Q-PCR.

Funding was provided by the Fondation Medic, the Swiss National Science Foundation, and the Canton de Genève.