期刊
COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s42003-021-01941-5
关键词
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资金
- Cell and Tissue Imaging Platform-PICT-IBiSA of the UMR3664, Institut Curie [ANR-10-INBS-04]
- Agence Nationale de la Recherche [ANR-10-EQPX-03, ANR-10-INBS-09-08]
- Canceropole Ile-de-France
- SiRIC-Curie program-SiRIC [INCa-DGOS-4654]
- Ligue Nationale contre le Cancer (Equipe labellisee Ligue)
- Labex DEEP [ANR-11-LABX-0044_DEEP, ANR-10-IDEX-0001-02]
- Horizon 2020 Marie Skodowska-Curie Actions Initial Training Network EpiSyStem [765966]
- la Fondation ARC pour la recherche sur le cancer
- Horizon 2020 Framework Programme for Research and Innovation (H2020 Marie Skodowska-Curie Actions) [798106]
- PSL
- [ERC-2015-ADG-694694]
- [ANR-16-CE12-0024]
- Marie Curie Actions (MSCA) [798106, 765966] Funding Source: Marie Curie Actions (MSCA)
The study establishes an inducible and reversible CENP-A overexpression system, combined with a switch in p53 status in human cell lines, revealing p53 as a key determinant of how CENP-A impacts cell state, cell identity, and therapeutic response. The findings show that CENP-A overexpression promotes senescence and radiosensitivity when p53 is functional, while promoting epithelial-mesenchymal transition when p53 is inactivated.
Tumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution. Jeffery et al. develop a system of inducible and reversible CENP-A overexpression, combined with a switch in p53 status in human cell lines. They find the tumor suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. This study suggests that CENP-A overexpression promotes the reprogramming of cell fates in the context of tumor evolution.
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