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KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance.
Hinohara, Kunihiko; Wu, Hua-Jun; Vigneau, Sébastien; McDonald, Thomas O; Igarashi, Kyomi J; Yamamoto, Kimiyo N; Madsen, Thomas; Fassl, Anne; Egri, Shawn B; Papanastasiou, Malvina; Ding, Lina; Peluffo, Guillermo; Cohen, Ofir; Kales, Stephen C; Lal-Nag, Madhu; Rai, Ganesha; Maloney, David J; Jadhav, Ajit; Simeonov, Anton; Wagle, Nikhil; Brown, Myles; Meissner, Alexander; Sicinski, Piotr; Jaffe, Jacob D; Jeselsohn, Rinath; Gimelbrant, Alexander A; Michor, Franziska; Polyak, Kornelia.
Afiliação
  • Hinohara K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Wu HJ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Vigneau S; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • McDonald TO; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;
  • Igarashi KJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Yamamoto KN; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Madsen T; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Fassl A; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Egri SB; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • Papanastasiou M; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • Ding L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Peluffo G; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Cohen O; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • Kales SC; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
  • Lal-Nag M; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
  • Rai G; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
  • Maloney DJ; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
  • Jadhav A; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
  • Simeonov A; National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
  • Wagle N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • Brown M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA.
  • Meissner A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • Sicinski P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Jaffe JD; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • Jeselsohn R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Gimelbrant AA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Michor F; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;
  • Polyak K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambr
Cancer Cell ; 34(6): 939-953.e9, 2018 12 10.
Article em En | MEDLINE | ID: mdl-30472020
Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Repressoras / Neoplasias da Mama / Proteínas Nucleares / Resistencia a Medicamentos Antineoplásicos / Histona Desmetilases com o Domínio Jumonji / Proteína 2 de Ligação ao Retinoblastoma / Transcriptoma Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Repressoras / Neoplasias da Mama / Proteínas Nucleares / Resistencia a Medicamentos Antineoplásicos / Histona Desmetilases com o Domínio Jumonji / Proteína 2 de Ligação ao Retinoblastoma / Transcriptoma Idioma: En Ano de publicação: 2018 Tipo de documento: Article