Authors: Gemma Serra-Bardenys, Enrique Blanco, Carmen Escudero-Iriarte, Queralt Serra-Camprubí, Jessica Querol, Laura Pascual-Reguant, Beatriz Morancho, Marta Escorihuela, Natalia Soledad Tissera, Anna Sabé, Luna Martín, Sandra Segura-Bayona, Gaetano Verde, Riccardo Aiese Cigliano, Alba Millanes-Romero, Celia Jerónimo, Joan Pau Cebrià-Costa, Paolo Nuciforo, Sara Simonetti, Cristina Viaplana, Rodrigo Dienstmann, Mafalda Oliveira, Vicente Peg, Travis H. Stracker, Joaquín Arribas, Francesc Canals, Josep Villanueva, Luciano Di Croce, Antonio García de Herreros, Tian V. Tian, Sandra Peiró

Publication: The FEBS Journal

Published: March, 2024



Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase homolog 2 (LOXL2). This histone modification is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here, we show that LOXL2 interacts with RuvB-Like 1 (RUVBL1), RuvB-Like 2 (RUVBL2), Actin-like protein 6A (ACTL6A), and DNA methyltransferase 1associated protein 1 (DMAP1), a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2-dependent chromatin compaction. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC-seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA-MB-231).