Research Papers:

The androgen receptor inhibits transcription of GPER1 by preventing Sp1 and Sp3 from binding to the promoters in prostate cancer cells

Austin McDermott, KyoungHyun Kim, Susan Kasper, Shuk-Mei Ho _ and Yuet-Kin Leung _

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Austin McDermott1, KyoungHyun Kim1, Susan Kasper1, Shuk-Mei Ho1,2,3 and Yuet-Kin Leung1,2,3

1 Department of Environmental Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA

2 Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA

3 Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

Correspondence to:

Yuet-Kin Leung, email: [email protected]
Shuk-Mei Ho, email: [email protected]

Keywords: GPR30; castration resistant; promoter; GPER1 spliced variants; transcription start site

Received: October 18, 2021     Accepted: December 08, 2021     Published: January 07, 2022

Copyright: © 2022 McDermott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


G-1, a GPER1 agonist, was shown to inhibit the growth of castration-resistant mouse xenografts but not their parental androgen-dependent tumors. It is currently unknown how the androgen receptor (AR) represses GPER1 expression. Here, we found that two GPER1 mRNA variants (GPER1v2 and GPER1v4) were transcriptionally repressed, not via transcript destabilization, by the androgen-activated AR. Although no AR binding was found in all active promoters near GPER1, data from promoter assays suggested that both variants’ promoters were inhibited by androgen treatment. Site-directed mutagenesis on Sp1/Sp3 binding sites revealed their role in supporting the basal expression of GPER1. Knockdown of Sp1 and Sp3 together but not separately repressed GPER1 expression whereas overexpression of both Sp1 and Sp3 together was required to alleviate AR repression of GPER1. Based on the chromatin immunoprecipitation data, Sp3 was found to bind to the promoters prior to the binding of Sp1 and RNA polymerase II. However, the binding of all three transcription factors was inhibited by DHT treatment. Concordantly, DHT treatment induced nuclear interactions between AR and Sp1 or Sp3. Taken together, these results indicate that AR represses transcription of GPER1 by binding to Sp1 and Sp3 independently to prevent their transactivation of the GPER1 promoters.

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