دورية أكاديمية
The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.
| العنوان: | The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis. |
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| المؤلفون: | Oser MG; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Sabet AH; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA., Gao W; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Chakraborty AA; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Schinzel AC; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA., Jennings RB; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Fonseca R; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA., Bonal DM; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02210, USA., Booker MA; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA., Flaifel A; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Novak JS; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Christensen CL; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA., Zhang H; Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA., Herbert ZT; Molecular Biology Core Facilities, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA., Tolstorukov MY; Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA., Buss EJ; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA., Wong KK; Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA., Bronson RT; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02215., Nguyen QD; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02210, USA., Signoretti S; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA., Kaelin WG Jr; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Massachusetts 02115, USA.; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. |
| المصدر: | Genes & development [Genes Dev] 2019 Dec 01; Vol. 33 (23-24), pp. 1718-1738. Date of Electronic Publication: 2019 Nov 14. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 8711660 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-5477 (Electronic) Linking ISSN: 08909369 NLM ISO Abbreviation: Genes Dev Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cold Spring Harbor, NY : Cold Spring Harbor Laboratory Press Original Publication: [Cold Spring Harbor, N.Y.] : Cold Spring Harbor Laboratory in association with the Genetical Society of Great Britain, [c1987- |
| مواضيع طبية MeSH: | Cell Differentiation/*genetics , Neuroendocrine Cells/*cytology , Receptors, Notch/*physiology , Retinoblastoma-Binding Protein 2/*metabolism , Signal Transduction/*genetics , Small Cell Lung Carcinoma/*enzymology, Animals ; Basic Helix-Loop-Helix Transcription Factors ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic/genetics ; Histone Demethylases/metabolism ; Humans ; In Vitro Techniques ; Mice ; Neuroendocrine Cells/pathology ; Small Cell Lung Carcinoma/physiopathology |
| مستخلص: | More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53 , and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A +/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC. (© 2019 Oser et al.; Published by Cold Spring Harbor Laboratory Press.) |
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| معلومات مُعتمدة: | United States HHMI Howard Hughes Medical Institute; R35 CA210068 United States CA NCI NIH HHS; K08 CA222657 United States CA NCI NIH HHS; P30 CA006516 United States CA NCI NIH HHS; K99 CA201618 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: ASCL1; CRISPR/Cas9; JARID1A; KDM5A; NOTCH; RBP2; SCLC; mouse model; neuroendocrine differentiation; small cell lung cancer |
| المشرفين على المادة: | 0 (ASCL1 protein, human) 0 (Basic Helix-Loop-Helix Transcription Factors) 0 (Receptors, Notch) EC 1.14.11.- (Histone Demethylases) EC 1.14.11.- (KDM5A protein, human) EC 1.14.11.27 (Retinoblastoma-Binding Protein 2) |
| تواريخ الأحداث: | Date Created: 20191116 Date Completed: 20191220 Latest Revision: 20200629 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6942053 |
| DOI: | 10.1101/gad.328336.119 |
| PMID: | 31727771 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1549-5477 |
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| DOI: | 10.1101/gad.328336.119 |