Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.

中文翻译：

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CDK7 和 MITF 抑制与黑色素瘤存活和药物耐受有关的转录程序

黑素瘤细胞表型在分化的黑素细胞和未分化的间充质样状态之间转换驱动转移和耐药性。CDK7 是基础转录因子 TFIIH 的丝氨酸/苏氨酸激酶。我们表明，黑色素细胞型黑色素瘤细胞去分化为间充质样细胞并获得对靶向治疗的耐受性是通过慢性抑制 CDK7 来实现的。除了出现间充质类型特征外，我们还确定了一个 GATA6 依赖性基因表达程序，其中包括分别参与黑色素瘤存活或靶向药物耐受性的基因，例如 AMIGO2 或 ABCG2。从机制上讲，我们表明 CDK7 驱动黑素细胞谱系转录因子 MITF 的表达，MITF 反过来与 GATA6 的内含子区域结合以抑制其在黑素细胞类型细胞中的表达。我们显示 GATA6 表达在患者来源的异种移植物的 MITF 低黑色素瘤细胞中被激活。总之，我们的数据显示了 MITF 在黑色素瘤中表征不佳的抑制功能如何参与分子级联调节转录程序的激活，该转录程序涉及黑色素瘤的存活和耐药性。