دورية أكاديمية
BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma.
| العنوان: | BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma. |
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| المؤلفون: | Watanabe J; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Department of Neurological Surgery, Brain Research Institute, Niigata University, Niigata, Japan., Clutter MR; Department of Molecular Biosciences., Gullette MJ; High Throughput Analysis Laboratory, and., Sasaki T; Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan., Uchida E; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Kaur S; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Mo Y; Institute for Cancer Genetics.; Department of Pediatrics, and.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, USA., Abe K; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA., Ishi Y; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA., Takata N; Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, and.; Simpson Querrey Institute for BioNanotechnology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Natsumeda M; Department of Neurological Surgery, Brain Research Institute, Niigata University, Niigata, Japan., Gadd S; Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA., Zhang Z; Institute for Cancer Genetics.; Department of Pediatrics, and.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, USA., Becher OJ; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Hashizume R; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.; Division of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Division of Pediatric Hematology and Oncology, Children's of Alabama, Birmingham, Alabama, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA. |
| المصدر: | The Journal of clinical investigation [J Clin Invest] 2024 May 21; Vol. 134 (13). Date of Electronic Publication: 2024 May 21. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation Original Publication: New Haven [etc.] American Society for Clinical Investigation. |
| مواضيع طبية MeSH: | Radiation Tolerance*/drug effects , Radiation Tolerance*/genetics , Histones*/metabolism , Histones*/genetics, Humans ; Animals ; Mice ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; DNA Repair/drug effects ; Glioma/radiotherapy ; Glioma/pathology ; Glioma/genetics ; Glioma/metabolism ; Glioma/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Brain Neoplasms/radiotherapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/drug therapy ; Radiation-Sensitizing Agents/pharmacology ; Transcription Factors/genetics ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; DNA Damage ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplasm Proteins/antagonists & inhibitors ; Bromodomain Containing Proteins ; Proteins |
| مستخلص: | Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG. |
| معلومات مُعتمدة: | R01 NS132344 United States NS NINDS NIH HHS; R01 CA277605 United States CA NCI NIH HHS; R01 CA258636 United States CA NCI NIH HHS; R01 CA197313 United States CA NCI NIH HHS; R01 NS126513 United States NS NINDS NIH HHS; P50 CA221747 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Brain cancer; Epigenetics; Oncology; Therapeutics; Translation |
| المشرفين على المادة: | 0 (Histones) 0 (Radiation-Sensitizing Agents) 0 (bromodomain and extra-terminal domain protein, human) 0 (Transcription Factors) 0 (Neoplasm Proteins) 0 (Bromodomain Containing Proteins) 0 (Proteins) |
| تواريخ الأحداث: | Date Created: 20240521 Date Completed: 20240701 Latest Revision: 20240710 |
| رمز التحديث: | 20240710 |
| مُعرف محوري في PubMed: | PMC11213469 |
| DOI: | 10.1172/JCI174794 |
| PMID: | 38771655 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1558-8238 |
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| DOI: | 10.1172/JCI174794 |