KDM5B links cellular transcriptome heterogeneity to therapy resistance (inDrop)

The KDM5B histone H3 lysine 4 (H3K4) demethylase has been implicated in therapy resistance in multiple cancer types including breast cancer, but the underlying mechanism is poorly defined. Here we show that inhibition of KDM5B activity increases sensitivity to anti-estrogens by modulating estrogen-receptor (ER) signaling. Conversely, acquired resistance to KDM5 inhibitors leads to gain of ER chromatin binding and estrogen-independent growth. Sequencing of barcoded cell populations and mathematical modeling demonstrate selection for pre-existent genetically distinct endocrine-resistant cells, while resistance to KDM5 inhibitors is a switch to an acquired epigenetic state. Rare resistant cells can already be detected by single cell RNA-seq prior to treatment. Inhibition of KDM5B in luminal ER+ cells increases H3K4me3 broad domains at promoters and decreases cellular transcriptional heterogeneity. Higher transcriptome heterogeneity is associated with higher KDM5B levels and poor prognosis in ER+ luminal breast tumors. Single cell transcriptome of parental and multiple resistant breast cancer cell lines

组蛋白H3赖氨酸4（H3K4）去甲基化酶KDM5B已被证实与包括乳腺癌在内的多种癌症的治疗耐药密切相关，但其介导耐药的潜在分子机制仍有待阐明。本研究发现，抑制KDM5B活性可通过调控雌激素受体（ER）信号通路，增强肿瘤细胞对抗雌激素疗法的敏感性。与之相反，对KDM5抑制剂产生获得性耐药的细胞株，会出现ER染色质结合能力增强及雌激素非依赖性生长的表型。通过对带条形码的细胞群体进行测序并结合数学建模，我们证实：内分泌治疗耐药的产生是对预先存在的、遗传背景各异的耐药细胞的筛选过程，而对KDM5抑制剂的耐药则是细胞转换为获得性表观遗传状态的结果。在治疗开始前，即可通过单细胞RNA测序检测到极少量的耐药细胞。在腔面型ER阳性乳腺癌细胞中抑制KDM5B活性，可显著增加启动子区域的H3K4me3宽结构域，并降低细胞的转录异质性。在ER阳性腔面型乳腺肿瘤中，更高的转录组异质性与KDM5B表达水平升高及患者不良预后显著相关。本数据集包含亲本及多株耐药乳腺癌细胞系的单细胞转录组数据。