Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.

溴结构域和末端结构域抑制剂（BETi）是治疗转移性黑色素瘤的有前景的药物，但其作用机制仍不清楚。在这里，我们研究了BETi的转录效应，并确定了AMIGO2（一种跨膜分子）作为黑色素瘤细胞存活所必需的BET靶基因。与人类黑色素细胞和痣相比，黑色素瘤细胞和组织中的 AMIGO2 表达上调，并且黑色素瘤细胞中 AMIGO2 沉默会诱导 G1/S 停滞，随后导致细胞凋亡。我们确定假激酶 PTK7 是 AMIGO2 相互作用因子，其功能受 AMIGO2 调节。表观基因组分析和基因组编辑表明AMIGO2受到黑色素瘤特异性 BRD2/4 结合启动子和超级增强子配置的调节。经过 BETi 处理，BET 被从这些调控元件中驱逐，导致 AMIGO2 沉默和 PTK7 蛋白水解过程的变化。总的来说，这项研究揭示了 BETi 对黑色素瘤治疗作用的潜在机制，并揭示了 AMIGO2-PTK7 轴作为转移性黑色素瘤的靶向途径。