Promoter‐specific transcriptional interference and c‐myc gene silencing by siRNAs in human cells
Open accessAbstract
Small interfering RNAs (siRNAs) directed to gene promoters can silence genes at the transcriptional level. siRNA-directed transcriptional silencing (RdTS) was first described in plants and yeasts and more recently in mammalian cells. RdTS has been associated with the induction of epigenetic changes and the formation of complexes containing RNA interference and chromatin-remodelling factors. Here, we show that a promoter-targeted siRNA inhibits transcription of the c-myc gene. Transcriptional silencing of c-myc did not involve changes of known epigenetic marks. Instead, the c-myc promoter-targeted siRNA interfered with transcription initiation blocking the assembly of the pre-initiation complex. Transcriptional interference depended on Argonaute 2 and a noncoding promoter-associated RNA initiated upstream and overlapping the transcription start site. Silencing of c-myc led to growth arrest, reduced clonogenic potential and senescence of c-myc over-expressing prostate cancer cells with minimal effect on normal cells. RNA-directed transcriptional interference may be a natural mechanism of transcriptional control and siRNAs targeting noncoding RNAs participating in this regulatory pathway could be valuable tools to control expression of deregulated genes in human diseases.
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Catapano's promoter-targeted siRNA inhibited transcription of the c-Myc gene, leading to growth arrest and cell senescence of human PC3 cells.
“Catapano’s group later demonstrated that a promoter-targeted siRNA, compound (243), could inhibit transcription of the c-Myc gene, leading to growth arrest and cell senescence of human PC3 cells.577”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [577]
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- Authors
- Napoli, S., Pastori, C., Magistri, M., Carbone, G. M., & Catapano, C. V.
- Affiliations
- Istituto Oncologico della Svizzera Italiana (CH)
- Corresponding author
- Catapano, Carlo V
- Venue
- The EMBO Journal
- Published
- 2009-05-21
- Volume
- 28
- Issue
- 12
- Pages
- 1708-1719
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2699364
- OpenAlex
- W1996954571
- Cited by
- 137
- References
- 50
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 1 · 2023: 7 · 2022: 5 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 16 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 10 · 2012: 16
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- siRNA, c-Myc, transcriptional silencing, transcription initiation, preinitiation complex, Argonaute 2, non-coding RNA, epigenetic silencing, chromatin remodeling, prostate cancer cells, cellular senescence, clonogenicity, growth arrest
- MeSH terms
- Humans, Promoter Regions, Genetic, RNA, Messenger, RNA, Neoplasm, Transcription, Genetic, Tumor Stem Cell Assay, Eukaryotic Initiation Factor-2, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Cellular Senescence, RNA, Untranslated, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques, Argonaute Proteins
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