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Etude du rôle du variant d'histone centromérique CENP-A dans le cancer

Year: 2024
Type: dissertation
Abstract: CENP-A (Centromere protein A) is a histone H3 variant incorporated into centromeric chromatin and essential for the proper segregation of human chromosomes to daughter cells during cell division. CENP-A overexpression, which promotes its mislocalization, is commonly observed in many cancers and correlates with aggressiveness of the disease. Interestingly, CENP-A transcription, while negatively regulated by the “tumor suppressor” p53, can evade this control. Thus, both p53-defective and p53 wild type cancers can display high levels of CENP-A. My goal was to understand how CENP-A overexpression and its ectopic localization participate in tumor evolution, considering the cellular context. Thus, I established a series of human cell lines with a tunable and reversible system to control CENP-A overexpression in various p53 contexts, that I analyzed under different conditions over time. Firstly, my work contributed to reveal how CENP-A overexpression affects cell cycle and identity in a manner that depends on the p53 status of the cells. Secondly, I identified a cell sub-population which, upon CENP-A overexpression, transitions towards mesenchymal states over time. This process, termed epithelial-mesenchymal transition (EMT), is a key driver of cancer progression and metastasis. Notably, by reversing CENP-A overexpression and erasing its ectopic localization, I could reverse the induced mesenchymal states. Furthermore, I found that CENP-A mislocalization promotes distinct EMT transcription programs. Altogether, these results suggest that CENP-A overexpression regulates cell plasticity in an epigenetic manner with important implications for cancer research.
Language: English
Subfield: Cell Biology
Open Access status: green
OpenAlex ID: W7046984384
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