KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Hinohara Kunihiko; Wu Hua-Jun; Vigneau Sebastien; 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

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KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

机译：KDM5组蛋白去甲基酶活性将细胞转录组异质性链接到治疗性的抵抗力

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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.

机译：KDM5组蛋白H3赖氨酸4脱甲基酶系列的成员与治疗性有关，包括乳腺癌中的内分泌抵抗力，但潜在机制定义不足。在这里，我们表明KDM5A / B的遗传缺失或KDM5活性的抑制通过调节雌激素受体（ER）信号传导并通过降低细胞转录组异质性来增加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 +乳腺肿瘤的预后差有关。单细胞RNA测序，细胞条码和数学建模表明，内分泌阻力是由于预先存在的遗传明显细胞的选择，而KDM5抑制剂抗性被获取。我们的研究结果突出了细胞表型异质性在治疗性抗性中的重要性，并鉴定KDM5A / B作为该过程的关键调节剂。

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《Cancer Cell》 |2018年第6期|共24页
作者
Hinohara Kunihiko; Wu Hua-Jun; Vigneau Sebastien; 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;
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作者单位

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Biostat &

Computat Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Biostat &

Computat Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Biostat &

Computat Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Biostat &

Computat Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Eli &

Edythe L Brd Inst MIT &

Harvard Cambridge MA 02139 USA;

Eli &

Edythe L Brd Inst MIT &

Harvard Cambridge MA 02139 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Natl Ctr Advancing Translat Sci Bethesda MD 20892 USA;

Natl Ctr Advancing Translat Sci Bethesda MD 20892 USA;

Natl Ctr Advancing Translat Sci Bethesda MD 20892 USA;

Natl Ctr Advancing Translat Sci Bethesda MD 20892 USA;

Natl Ctr Advancing Translat Sci Bethesda MD 20892 USA;

Natl Ctr Advancing Translat Sci Bethesda MD 20892 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Harvard Univ Dept Stem Cell &

Regenerat Biol Cambridge MA 02138 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Eli &

Edythe L Brd Inst MIT &

Harvard Cambridge MA 02139 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Canc Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Biostat &

Computat Biol Boston MA 02215 USA;

Dana Farber Canc Inst Dept Med Oncol Boston MA 02215 USA;

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正文语种 eng
中图分类肿瘤学;
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专利

1. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance (vol 34, pg 939, 2018) [J] . Hinohara Kunihiko, Wu Hua-Jun, Vigneau Sebastien, Cancer Cell . 2019,第2期

机译：KDM5组蛋白脱甲基酶活性将细胞转录组异质性与治疗性相连（Vol 34，PG 939,2018）
2. Kdm5/Lid Regulates Chromosome Architecture in Meiotic Prophase I Independently of Its Histone Demethylase Activity [J] . Liudmila Zhaunova, Hiroyuki Ohkura, Manuel Breuer PLoS Genetics . 2016,第8期

机译：Kdm5 / Lid独立于其组蛋白去甲基化酶活性调节减数分裂前期I中的染色体结构。
3. The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction [J] . Helen M. Belalcazar, Emily L. Hendricks, Sumaira Zamurrad, Cell Reports . 2021,第7期

机译：组蛋白去甲基酶KDM5是果蝇神经肌肉交界处的突触结构和功能所必需的
4. Towards an in Vitro Model of Anti-Therapeutic Resistance: Cellular Drug Efflux Pump Systems in Supported Lipid Bilayer/Nanostructure Hybrid Structures [C] . Bin He, M. Lane Gilchrist American Institute of Chemical Engineers Annual Meeting . 2007

机译：朝向抗治疗性的体外模型：支撑脂质双层/纳米结构杂交结构中的细胞药物流出泵系统
5. Discovery and biochemical evaluation of chemical probes for the study of jumonji-C domain containing histone demethylases and antibiotic resistance machinery in MRSA [D] . Podoll, Jessica Danielle 2015

机译：用于研究MRSA中含有组蛋白去甲基化酶和抗生素抗性机制的jumonji-C域的化学探针的发现和生化评估
6. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance [O] . Kunihiko Hinohara, Hua-Jun Wu, Sébastien Vigneau, -1

机译：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
7. KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance [O] . Kunihiko Hinohara, Hua-Jun Wu, Sébastien Vigneau, 2018

机译：KDM5组蛋白去甲基酶活性将细胞转录组异质性链接到治疗性的抵抗力
8. Targeting Histone Demethylase GASC1/JMJD2C/KDM4C as a Novel Therapeutic Strategy in Castration-Resistant Prostate Cancer. [R] . Yang, Z. 2013

机译：靶向组蛋白去甲基化酶GasC1 / JmJD2C / KDm4C作为去势抵抗性前列腺癌的新型治疗策略。

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

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