Retinoic Acid (RA) Regulates 17β-Hydroxysteroid Dehydrogenase Type 2 Expression in Endometrium: Interaction of RA Receptors with Specificity Protein (SP) 1/SP3 for Estradiol Metabolism
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CONTEXT: The enzyme 17beta-hydroxysteroid dehydrogenase type 2 (HSD17B2) exerts a local antiestrogenic effect by metabolizing biologically active estradiol to inactive estrone in endometrial epithelial cells. Retinoic acid (RA) induces HSD17B2 expression, but the underlying mechanism is not known. OBJECTIVE: Our objective was to elucidate the molecular mechanisms responsible for HSD17B2 expression in human endometrial cells. METHOD: Human endometrial Ishikawa and RL95-2 cell lines were cultured in the presence or absence of RA to analyze endogenous HSD17B2 expression, transcription factor complex formation, and promoter activity. RESULTS: RA induced HSD17B2 mRNA levels in a dose- and time-dependent manner in endometrial cells. The RA antagonist ANG11273 abolished RA-induced HSD17B2 expression. Small interfering RNA ablation of RA receptor (RAR)alpha or retinoid X receptor (RXR)alpha completely blocked RA-induced HSD17B2 gene expression. Analysis of serial deletion and site-directed mutants of the HSD17B2 promoter fused to a reporter gene indicated that RA induction requires a cis-regulatory sequence that binds the specificity protein (SP) class of transcription factors. Chromatin-immunoprecipitation-PCR and gel-shift assays showed that RARalpha/RXRalpha and SP1/SP3 interact with this HSD17B2 promoter sequence. Small interfering RNA ablation of SP1 and SP3 expression markedly decreased HSD17B2 basal expression and blocked RA-induced expression. Finally, immunoprecipitationimmunoblotting demonstrated RA-induced interactions between RARalpha/RXRalpha and SP1/SP3 in intact endometrial cells. CONCLUSIONS: In endometrial epithelial cells, RA stimulates formation of a multimeric complex comprised of RARalpha/RXRalpha tethered to transcription factors SP1 and SP3 on the HSD17B2 promoter. Assembly of this transcriptional complex is necessary for RA induction of HSD17B2 expression and may be an important mechanism for local estradiol inactivation in the endometrium.
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Progesterone via PGR induces retinoic acid production in endometrial stromal cells, which then acts on epithelial cells to induce HSD17B2 expression.
“Progesterone via PGR induces retinoic acid production in endometrial stromal cells, which then acts on epithelial cells to induce HSD17B2 expression”
From Endometriosis and nuclear receptors (2019) · cites this paper as Cheng et al., 2008
The introduction (p. 1) reports that progesterone indirectly induces epithelial HSD17B2 through stromal-secreted factors and that retinoids are among factors secreted by stromal cells. The Results and Conclusions (p. 1) show that retinoic acid induces HSD17B2 in endometrial epithelial cells. The paper does not establish the claimed link that progesterone, via PGR, induces retinoic acid production in stromal cells. (LLM, conf=0.88)
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Self-citation
- Authors
- Cheng, Y.-H., Yin, P., Xue, Q., Yilmaz, B., Dawson, M. I., & Bulun, S. E.
- Affiliations
- Northwestern University (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-05
- Volume
- 93
- Issue
- 5
- Pages
- 1915-1923
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2386682
- OpenAlex
- W2152628855
- Cited by
- 71
- References
- 36
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 4 · 2012: 3
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD040093, HD 40093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- retinoic acid, 17β-hydroxysteroid dehydrogenase type 2, HSD17B2, endometrium, retinoic acid receptor alpha, retinoid X receptor alpha, Sp1, estradiol metabolism, estrone, gene expression regulation, transcriptional complex
- MeSH terms
- Endometrium, Epithelial Cells, Estradiol, Estradiol Dehydrogenases, Female, Humans, Promoter Regions, Genetic, Tretinoin, 17-Hydroxysteroid Dehydrogenases, Gene Expression Regulation, Enzymologic, Mutagenesis, Site-Directed, Sp1 Transcription Factor, Receptors, Retinoic Acid, RNA, Small Interfering, Cell Line, Tumor, Sp3 Transcription Factor
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