Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

上皮-间质转化 (EMT) 是一个被癌细胞劫持以调节增殖、迁移和应激反应的发育过程。虽然激酶信号被认为是 EMT 驱动因素，但上皮-间质相互转化的分子机制尚不完全清楚。在这里，我们表明染色质调节剂对 EMT 相互转换的影响比激酶的影响更广泛。通过结合 EMT 的药理学调节、合成基因追踪和 CRISPR 干扰筛选，我们发现了少数激酶和几种染色质重塑者、作者和读者在肺癌细胞中控制稳态 EMT。ARID1A、DOT1L、BRD2 和 ZMYND8 的缺失对上皮-间质相互转化具有不确定性，有时甚至相反的后果。与 RNAPII 和 AP-1 一起，这些拮抗的看门人控制着活性增强子的染色质，包括泛癌 EMT 特征基因，能够对解剖学上不同的肿瘤进行超分类。因此，我们的数据揭示了癌细胞可塑性转录控制的一般原则，并为系统探索肿瘤状态特异性治疗中的染色质调节剂提供了一个平台。