Year: 2021
Type: article
Abstract: 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.
Source: Communications Biology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,290
Funders: Infrastructures en Biologie Santé et Agronomie, Equipex, Agence Nationale de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Institut National Du Cancer, Direction Générale de l’offre de Soins, Horizon 2020 Framework Programme, H2020 Marie Skłodowska-Curie Actions
Awards: G1554707310, G1592728031, G2189472788, G2450198060, Chromatin organization and mitotic inheritance of epigenetic states: genome-wide dynamics of H3.1 and H3.3 histone variants during DNA replication, G2579310621, G2580753410, Paris Sciences et Lettres, G271172329, Epigenetics and System Biology of Stem cells and Reprogramming, Chaperone-Histone Determinants of Cell Identity, Lineage Fate and Transitions, G3587764255, Equipement de biologie intégrative du cancer pour une médecine personnalisée, G381665449, G3898041522, G4072984709, G4190806336, G449165211, G4683787787, G471331628, G5125889110, G5420063140, Ecole Universitaire de Recherche Interdisciplinaire de Paris, G5788626477, G586987437, G6048653459, G6062526893, G705061367, G7240651115, G7358480839, G7398299134, G7428494302, G7777646733, G782245399, G786270660, G7913098808, G7999552054, Développement, Epigénèse, Epigénétique et potentiel de vie, G8301460240, G8510727784, G8916787474
OpenAlex ID: W3139454364