KDM5组蛋白去甲基化酶活性将细胞转录组异质性与治疗耐药性联系起来。,Cancer Cell

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KDM5组蛋白去甲基化酶活性将细胞转录组异质性与治疗耐药性联系起来。
Cancer Cell ( IF 48.8 ) Pub Date : 2018-11-21 , DOI: 10.1016/j.ccell.2018.10.014
Kunihiko Hinohara ₁ , Hua-Jun Wu ₂ , Sébastien Vigneau ₃ , Thomas O McDonald ₄ , Kyomi J Igarashi ₃ , Kimiyo N Yamamoto ₂ , Thomas Madsen ₂ , Anne Fassl ₃ , Shawn B Egri ₅ , Malvina Papanastasiou ₅ , Lina Ding ₁ , Guillermo Peluffo ₁ , Ofir Cohen ₆ , Stephen C Kales ₇ , Madhu Lal-Nag ₇ , Ganesha Rai ₇ , David J Maloney ₇ , Ajit Jadhav ₇ , Anton Simeonov ₇ , Nikhil Wagle ₈ , Myles Brown ₉ , Alexander Meissner ₁₀ , Piotr Sicinski ₃ , Jacob D Jaffe ₅ , Rinath Jeselsohn ₁ , Alexander A Gimelbrant ₃ , Franziska Michor ₁₁ , Kornelia Polyak ₁₂

Affiliation

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
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.
National Center for Advancing Translational Sciences, Bethesda, MD 20892, USA.
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.
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.
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.
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; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Ludwig Center at Harvard, Boston, MA 02215, USA.
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, Cambridge, MA 02139, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA.

KDM5组蛋白H3赖氨酸4脱甲基酶家族的成员与治疗抗性相关，包括乳腺癌的内分泌抗性，但潜在的机制尚不明确。在这里，我们显示KDM5A / B的基因缺失或KDM5活性的抑制通过调节雌激素受体（ER）信号传导和降低细胞转录组异质性而增加了对抗雌激素的敏感性。较高的KDM5B表达水平与较高的转录组异质性和ER +乳腺肿瘤的预后不良有关。单细胞RNA测序，细胞条形码和数学模型表明，内分泌抗性是由于选择了已有的遗传上不同的细胞，而获得了KDM5抑制剂的抗性。

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更新日期：2018-11-24

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