The Human Tumor Antigen PRAME Is a Dominant Repressor of Retinoic Acid Receptor Signaling
Open accessAbstract
Retinoic acid (RA) induces proliferation arrest, differentiation, and apoptosis, and defects in retinoic acid receptor (RAR) signaling have been implicated in cancer. The human tumor antigen PRAME is overexpressed in a variety of cancers, but its function has remained unclear. We identify here PRAME as a dominant repressor of RAR signaling. PRAME binds to RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME is present at RAR target promoters and inhibits RA-induced differentiation, growth arrest, and apoptosis. Conversely, knockdown of PRAME expression by RNA interference in RA-resistant human melanoma restores RAR signaling and reinstates sensitivity to the antiproliferative effects of RA in vitro and in vivo. Our data suggest that overexpression of PRAME frequently observed in human cancers confers growth or survival advantages by antagonizing RAR signaling.
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In contrast to the classical p160 coregulators, RIP140 and PRAME inhibit the transcriptional activity of RARs through the recruitment of HDACs and PcG proteins respectively.
“In contrast to the classical p160 coregulators, RIP140 and PRAME inhibit the transcriptional activity of RARs through the recruitment of HDACs ( 108 ) and PcG proteins ( 63 ) respectively.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [63]
At the end of the transcriptional response, liganded RARs have been shown to recruit unconventional coregulators with LxxLL motifs, such as RIP140 and PRAME.
“At the end of the transcriptional response, liganded RARs have been shown to recruit unconventional coregulators with LxxLL motifs, such as RIP140 and PRAME ( Fig. 4C ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [63]
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- Authors
- Epping, M. T., Wang, L., Edel, M. J., Carlée, L., Hernandez, M., & Bernards, R.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Bernards, René
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2005-09
- Volume
- 122
- Issue
- 6
- Pages
- 835-847
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2125685908
- Cited by
- 432
- References
- 3
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 27 · 2023: 35 · 2022: 27 · 2021: 20 · 2020: 25 · 2019: 16 · 2018: 14 · 2017: 12 · 2016: 18 · 2015: 18 · 2014: 15 · 2013: 26 · 2012: 15
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- PRAME, retinoic acid receptor signaling, retinoic acid, tumor antigens, Polycomb group proteins, transcriptional repression, melanoma, retinoic acid resistance, apoptosis, cell differentiation
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Antigens, Neoplasm, Cell Differentiation, DNA-Binding Proteins, Humans, Ligands, Melanoma, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Protein Binding, Repressor Proteins, Sensitivity and Specificity, Transcription Factors, Transplantation, Heterologous, Tretinoin, Signal Transduction, Apoptosis, Receptors, Retinoic Acid, RNA Interference, Cell Line, Tumor, Cell Proliferation, Mice, Polycomb Repressive Complex 2
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