HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer
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Significance: The plasticity of Polycomb repressive complex 2 (PRC2) in the context of tumorigenesis has remained a subject of contention. Here we demonstrate that the equilibrium between the oncogenic and tumor-suppressive activity of PRC2 in promoting breast cancer invasion is tightly regulated by hypoxia-inducible factor 1-α. PRC2 acts as a tumor-suppressor barrier to the hypoxia-driven invasion pathway, and the impaired PRC2 activity upon hypoxia promotes a chromatin switch at proinvasion matrix metalloproteinase gene loci. The study fundamentally changed our understanding of the role of PRC2 in breast cancer and also identified a previously unidentified function of enhancer of zeste 2 to complex with Forkhead box M1 to promote cancer invasion.
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The hypoxia gene signature is inversely correlated with immune effector genes (IFNG, TNF, GZMB, PRF1), IFNγ-responsive genes, and TIL-associated genes in TNBC (n = 99) in the TCGA dataset.
“data analysis of The Cancer Genome Atlas (TCGA) dataset11 identified that hypoxic gene signature, which includes commonly documented hypoxia-responsive genes26, was inversely correlated with immune effector genes (IFNG, TNF, GZMB, PRF1), IFNγ-responsive genes, as well as genes associated with tumor-infiltrating lymphocytes (TILs) in TNBC (n = 99) (also referred as a basal subtype of breast cancer)”
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Research works printed but not linked: 1
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Self-citation
- Authors
- Mahara, S., Lee, P. L., Feng, M., Tergaonkar, V., Chng, W. J., & Yu, Q.
- Affiliations
- Agency for Science, Technology and Research (SG)
- South Australia Pathology (AU)
- National University of Singapore (SG)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-06-14
- Volume
- 113
- Issue
- 26
- Pages
- E3735-44
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4932959
- OpenAlex
- W2429341351
- Cited by
- 87
- References
- 66
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 11 · 2023: 13 · 2022: 9 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 6 · 2017: 5 · 2016: 1
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- Agency for Science, Technology and Research
- Cancer Science Institute of Singapore, National University of Singapore
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HIF1A, EZH2, polycomb repressive complex 2, breast cancer, triple-negative breast cancer, FOXM1, SUZ12, EED, matrix metalloproteinases, tumor invasion, hypoxia, tumor suppressor function, oncogenic function
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Breast Neoplasms, Humans, Cell Line, Tumor, Cell Proliferation, Hypoxia-Inducible Factor 1, alpha Subunit, Polycomb Repressive Complex 2
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