3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. Nuclear deformability plays a critical role in cancer cell invasion through confined spaces; however, the direct impact of epigenetic change...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | European Journal of Cell Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171933523000584 |
| _version_ | 1797680822947414016 |
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| author | Raquel González-Novo Ana de Lope-Planelles María Pilar Cruz Rodríguez África González-Murillo Elena Madrazo David Acitores Mario García de Lacoba Manuel Ramírez Javier Redondo-Muñoz |
| author_facet | Raquel González-Novo Ana de Lope-Planelles María Pilar Cruz Rodríguez África González-Murillo Elena Madrazo David Acitores Mario García de Lacoba Manuel Ramírez Javier Redondo-Muñoz |
| author_sort | Raquel González-Novo |
| collection | DOAJ |
| description | Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. Nuclear deformability plays a critical role in cancer cell invasion through confined spaces; however, the direct impact of epigenetic changes on the nuclear deformability of leukemic cells remains unclear. Here, we characterized how 3D collagen matrix conditions induced H3K4 methylation in ALL cell lines and clinical samples. We used specific shRNA and chemical inhibitors to target WDR5 (a core subunit involved in H3K4 methylation) and determined that targeting WDR5 reduced the H3K4 methylation induced by the 3D environment and the invasiveness of ALL cells in vitro and in vivo. Intriguingly, targeting WDR5 did not reduce the adhesion or the chemotactic response of leukemia cells, suggesting a different mechanism by which H3K4 methylation might govern ALL cell invasiveness. Finally, we conducted biochemical, and biophysical experiments to determine that 3D environments promoted the alteration of the chromatin, the morphology, and the mechanical behavior of the nucleus in ALL cells. Collectively, our data suggest that 3D environments control an upregulation of H3K4 methylation in ALL cells, and targeting WDR5 might serve as a promising therapeutic target against ALL invasiveness in vivo. |
| first_indexed | 2024-03-11T23:35:52Z |
| format | Article |
| id | doaj.art-51c38b50b2bf4a0a9e249892f4f92e07 |
| institution | Directory Open Access Journal |
| issn | 0171-9335 |
| language | English |
| last_indexed | 2024-03-11T23:35:52Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Cell Biology |
| spelling | doaj.art-51c38b50b2bf4a0a9e249892f4f92e072023-09-20T04:20:39ZengElsevierEuropean Journal of Cell Biology0171-93352023-09-0110231513433D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cellsRaquel González-Novo0Ana de Lope-Planelles1María Pilar Cruz Rodríguez2África González-Murillo3Elena Madrazo4David Acitores5Mario García de Lacoba6Manuel Ramírez7Javier Redondo-Muñoz8Department of Molecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, SpainDepartment of Molecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, SpainDepartment of Molecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, SpainOncolohematology Unit, Hospital Universitario Niño Jesús, Madrid, Spain; Health Research Institute La Princesa, Madrid, SpainDepartment of Molecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, SpainInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, AustriaBioinformatics and Biostatistics Unit, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, SpainOncolohematology Unit, Hospital Universitario Niño Jesús, Madrid, Spain; Health Research Institute La Princesa, Madrid, SpainDepartment of Molecular Medicine, Centro de Investigaciones Biológicas Margarita Salas (CIB Margarita Salas-CSIC), Madrid, Spain; Corresponding author.Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. Nuclear deformability plays a critical role in cancer cell invasion through confined spaces; however, the direct impact of epigenetic changes on the nuclear deformability of leukemic cells remains unclear. Here, we characterized how 3D collagen matrix conditions induced H3K4 methylation in ALL cell lines and clinical samples. We used specific shRNA and chemical inhibitors to target WDR5 (a core subunit involved in H3K4 methylation) and determined that targeting WDR5 reduced the H3K4 methylation induced by the 3D environment and the invasiveness of ALL cells in vitro and in vivo. Intriguingly, targeting WDR5 did not reduce the adhesion or the chemotactic response of leukemia cells, suggesting a different mechanism by which H3K4 methylation might govern ALL cell invasiveness. Finally, we conducted biochemical, and biophysical experiments to determine that 3D environments promoted the alteration of the chromatin, the morphology, and the mechanical behavior of the nucleus in ALL cells. Collectively, our data suggest that 3D environments control an upregulation of H3K4 methylation in ALL cells, and targeting WDR5 might serve as a promising therapeutic target against ALL invasiveness in vivo.http://www.sciencedirect.com/science/article/pii/S0171933523000584Cell migrationEpigeneticsNuclear deformabilityAcute lymphoblastic leukemiaCell invasion |
| spellingShingle | Raquel González-Novo Ana de Lope-Planelles María Pilar Cruz Rodríguez África González-Murillo Elena Madrazo David Acitores Mario García de Lacoba Manuel Ramírez Javier Redondo-Muñoz 3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells European Journal of Cell Biology Cell migration Epigenetics Nuclear deformability Acute lymphoblastic leukemia Cell invasion |
| title | 3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells |
| title_full | 3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells |
| title_fullStr | 3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells |
| title_full_unstemmed | 3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells |
| title_short | 3D environment controls H3K4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells |
| title_sort | 3d environment controls h3k4 methylation and the mechanical response of the nucleus in acute lymphoblastic leukemia cells |
| topic | Cell migration Epigenetics Nuclear deformability Acute lymphoblastic leukemia Cell invasion |
| url | http://www.sciencedirect.com/science/article/pii/S0171933523000584 |
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