Disruption of the epigenetic regulator BAP1 drives chromatin remodeling leading to the emergence of cells with breast cancer stem cell properties and aberrant glycosylation.

Araujo, M. G. d. S.; Salle, A.; Cahais, V.; Renard, C.; Cuenin, C.; Poubel, C. P.; Keita, S.; Mosler, T.; Carreira, C.; Levy, G. G.; Parres, L.; Bourova-Flin, E.; Rousseaux, S.; Khochbin, S.; Ghantous, A.; Habazin, S.; Pucic-Bakovic, M.; Cosset, E.; Lauc, G.; Herceg, Z.; Khoueiry, R.

doi:10.1101/2024.12.12.628129

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bioRxiv · 10.1101/2024.12.12.628129

Disruption of the epigenetic regulator BAP1 drives chromatin remodeling leading to the emergence of cells with breast cancer stem cell properties and aberrant glycosylation.

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Abstract

BackgroundEpigenetic regulator genes play critical roles in controlling cell identity and are frequently disrupted in breast cancers, suggesting a key driver role in this disease and its associated phenotypes. However, specific epigenetic drivers (epidrivers) of mammary cell plasticity and their mechanistic contributions to this phenotype are poorly characterized. MethodsTo identify potential epidrivers of the emergence of mesenchymal breast cancer stem cell-like phenotypes in non-tumorigenic mammary cells, we employed a CRISPR/Cas9 loss-of-function screening strategy targeting epigenetic regulator genes. This approach was followed by an in-depth validation and characterization of epigenomic, transcriptomic, proteomic and phenotypic changes resulting from the disruption of the putative epidriver gene BAP1. ResultsOur investigation revealed that loss of the histone deubiquitinase BAP1 impacts cellular processes associated with breast cancer cell plasticity such as epithelial-to-mesenchymal transition (EMT) and actin cytoskeleton organization. In addition, we unveiled that BAP1 loss resulted in an overall less permissive chromatin and downregulated gene expression, impacting programs that control cellular glycosylation and leading to decreased glycan abundance and complexity. BAP1 rescue restored the expression of several deregulated genes in a catalytic activity-dependent manner, suggesting that BAP1-mediated cell identity and glycosylation regulation are largely dependent on its histone deubiquitinase activity. ConclusionsOverall, our results point to BAP1 disruption as a driver of mammary cell plasticity and reveal a novel role of BAP1 as an epigenetic regulator of cellular glycosylation.

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Araujo, M. G. d. S., Salle, A., Cahais, V., Renard, C., Cuenin, C., Poubel, C. P., Keita, S., Mosler, T., Carreira, C., Levy, G. G., Parres, L., Bourova-Flin, E., Rousseaux, S., Khochbin, S., Ghantous, A., Habazin, S., Pucic-Bakovic, M., Cosset, E., Lauc, G., Herceg, Z., Khoueiry, R.. 2024-12-13. Disruption of the epigenetic regulator BAP1 drives chromatin remodeling leading to the emergence of cells with breast cancer stem cell properties and aberrant glycosylation.. https://doi.org/10.1101/2024.12.12.628129

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