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Loss of miR-200 Inhibition of Suz12 Leads to Polycomb-Mediated Repression Required for the Formation and Maintenance of Cancer Stem Cells
Open accessAbstract
In an inducible oncogenesis model, the miR-200 family is inhibited during CSC formation but not transformation, and inhibition of miR-200b increases CSC formation. Interestingly, miR-200b directly targets Suz12, a subunit of a polycomb repressor complex (PRC2). Loss of miR-200 during CSC formation increases Suz12 expression, Suz12 binding, H3-K27 trimethylation, and Polycomb-mediated repression of the E-cadherin gene. miR-200b expression or Suz12 depletion blocks the formation and maintenance of mammospheres, and in combination with chemotherapy suppresses tumor growth and prolongs remission in mouse xenografts. Conversely, ectopic expression of Suz12 in transformed cells is sufficient to generate CSCs. The miR-200b-Suz12-cadherin pathway is important for CSC growth and invasive ability in genetically distinct breast cancer cells, and its transcriptional signature is observed in metastatic breast tumors. The interaction between miR-200 and Suz12 is highly conserved, suggesting that it represents an ancient regulatory mechanism to control the growth and function of stem cells.
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Metadata
- Authors
- Iliopoulos, D., Lindahl-Allen, M., Polytarchou, C., Hirsch, H. A., Tsichlis, P. N., & Struhl, K.
- Affiliations
- Harvard University (US)
- Tufts Medical Center (US)
- Corresponding author
- Struhl, Kevin
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 39
- Issue
- 5
- Pages
- 761-772
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2938080
- OpenAlex
- W2050306367
- Cited by
- 399
- References
- 53
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 14 · 2020: 21 · 2019: 29 · 2018: 16 · 2017: 24 · 2016: 23 · 2015: 34 · 2014: 51 · 2013: 52 · 2012: 41
- FWCI
- 14.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- China Scholarship Council
- National Cancer Institute (R01CA107486, CA 57486, CA107486, R01CA057436)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- miR-200b, SUZ12, cancer stem cells, polycomb repressive complex 2, H3K27me3, E-cadherin, breast cancer, mammospheres, chemoresistance, metastasis, microRNA target regulation
- MeSH terms
- Animals, Breast Neoplasms, Carrier Proteins, Female, Humans, Mice, Nude, Neoplasm Proteins, Neoplasm Transplantation, Nuclear Proteins, Repressor Proteins, RNA, Neoplasm, Transcription Factors, Transplantation, Heterologous, Neoplastic Stem Cells, Cadherins, MicroRNAs, Cell Line, Tumor, Mice, Polycomb-Group Proteins, Polycomb Repressive Complex 2
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