H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells
Summary: Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724000354 |
| _version_ | 1797291766204858368 |
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| author | Katarzyna B. Leszczynska Amanda Freitas-Huhtamäki Chinchu Jayaprakash Monika Dzwigonska Francisca N.L. Vitorino Cynthia Horth Kamil Wojnicki Bartlomiej Gielniewski Paulina Szadkowska Beata Kaza Javad Nazarian Maciej K. Ciolkowski Joanna Trubicka Wieslawa Grajkowska Benjamin A. Garcia Jacek Majewski Bozena Kaminska Jakub Mieczkowski |
| author_facet | Katarzyna B. Leszczynska Amanda Freitas-Huhtamäki Chinchu Jayaprakash Monika Dzwigonska Francisca N.L. Vitorino Cynthia Horth Kamil Wojnicki Bartlomiej Gielniewski Paulina Szadkowska Beata Kaza Javad Nazarian Maciej K. Ciolkowski Joanna Trubicka Wieslawa Grajkowska Benjamin A. Garcia Jacek Majewski Bozena Kaminska Jakub Mieczkowski |
| author_sort | Katarzyna B. Leszczynska |
| collection | DOAJ |
| description | Summary: Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone. |
| first_indexed | 2024-03-07T19:42:27Z |
| format | Article |
| id | doaj.art-590589af8239422c9bd340fc8f43c4fa |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-07T19:42:27Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-590589af8239422c9bd340fc8f43c4fa2024-02-29T05:18:43ZengElsevierCell Reports2211-12472024-02-01432113707H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cellsKatarzyna B. Leszczynska0Amanda Freitas-Huhtamäki1Chinchu Jayaprakash2Monika Dzwigonska3Francisca N.L. Vitorino4Cynthia Horth5Kamil Wojnicki6Bartlomiej Gielniewski7Paulina Szadkowska8Beata Kaza9Javad Nazarian10Maciej K. Ciolkowski11Joanna Trubicka12Wieslawa Grajkowska13Benjamin A. Garcia14Jacek Majewski15Bozena Kaminska16Jakub Mieczkowski17Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland; Corresponding authorLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USADepartment of Human Genetics, McGill University, Montreal, QC, CanadaLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandCenter for Genetic Medicine Research, Children’s National Hospital, Washington, DC, USA; Department of Pediatrics, University Children’s Hospital Zürich, Zürich, SwitzerlandChildren’s Memorial Health Institute, Warsaw, PolandChildren’s Memorial Health Institute, Warsaw, PolandChildren’s Memorial Health Institute, Warsaw, PolandDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USADepartment of Human Genetics, McGill University, Montreal, QC, CanadaLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland; 3P-Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland; Corresponding authorSummary: Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone.http://www.sciencedirect.com/science/article/pii/S2211124724000354CP: Cancer |
| spellingShingle | Katarzyna B. Leszczynska Amanda Freitas-Huhtamäki Chinchu Jayaprakash Monika Dzwigonska Francisca N.L. Vitorino Cynthia Horth Kamil Wojnicki Bartlomiej Gielniewski Paulina Szadkowska Beata Kaza Javad Nazarian Maciej K. Ciolkowski Joanna Trubicka Wieslawa Grajkowska Benjamin A. Garcia Jacek Majewski Bozena Kaminska Jakub Mieczkowski H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells Cell Reports CP: Cancer |
| title | H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells |
| title_full | H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells |
| title_fullStr | H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells |
| title_full_unstemmed | H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells |
| title_short | H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells |
| title_sort | h2a z histone variants facilitate hdaci dependent removal of h3 3k27m mutant protein in pediatric high grade glioma cells |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724000354 |
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