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.
Cancer Cell. 2018 Dec 10;34(6):939-953.e9. doi: 10.1016/j.ccell.2018.10.014. Epub 2018 Nov 21.
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.
KDM5 组蛋白 H3 赖氨酸 4 去甲基酶家族的成员与治疗耐药性有关，包括乳腺癌的内分泌耐药性，但潜在机制尚不清楚。在这里，我们表明，KDM5A/B 的基因缺失或 KDM5 活性的抑制通过调节雌激素受体 (ER) 信号和降低细胞转录组异质性来增加对抗雌激素药物的敏感性。更高的 KDM5B 表达水平与 ER 阳性乳腺癌中更高的转录组异质性和预后不良相关。单细胞 RNA 测序、细胞条形码和数学建模表明，内分泌耐药性是由于选择预先存在的遗传上不同的细胞，而 KDM5 抑制剂耐药性是后天获得的。我们的研究结果强调了细胞表型异质性在治疗耐药性中的重要性，并确定 KDM5A/B 是该过程的关键调节剂。
