LOXL2-mediated chromatin compaction is required to maintain the oncogenic properties of triple-negative breast cancer cells.

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

Journal: The FEBS journal 2024;291(11):2423-2448

PMID: 38451841

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Abstract

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).

Address: Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.; Institut Bonanova FP Sanitaria, Consorci Mar Parc de Salut de Barcelona, Spain.; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Spain.; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.; The Francis Crick Institute, London, UK.; Sequentia Biotech SL, Barcelona, Spain.; Institute for Research in Biomedicine (IRB Barcelona) and Barcelona Institute of Science and Technology, Spain.; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Spain.; Institut de Recherches Cliniques de Montréal, Canada.; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.; Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.; Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.; Centro de Investigación Biomédica en Red en Oncología (CIBERONC), Barcelona, Spain.; Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, USA.; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.; Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.; Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.; Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

DOI: 10.1111/febs.17112

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MeSH Terms: Female, Humans, Amino Acid Oxidoreductases, Cell Line, Tumor, Chromatin, DNA Helicases, Gene Expression Regulation, Neoplastic, Heterochromatin, Histones, Triple Negative Breast Neoplasms