超级增强子 (SE) 是增强子的延伸，确保与细胞功能相关的关键基因的高水平表达。癌症特异性 SE 驱动基因的鉴定是开发创新治疗策略的有力手段。在这里，我们鉴定了 MITF/SOX10/TFIIH 依赖性 SE 在广泛的黑色素瘤细胞中促进 BAHCC1 的表达。 BAHCC1 在转移性黑色素瘤中高表达，是肿瘤植入、生长和扩散所必需的。综合基因组学分析表明，BAHCC1 是一种转录调节因子，控制 E2F/KLF 依赖性细胞周期和 DNA 修复基因的表达。 BAHCC1 在这些基因的启动子处与含有 BRG1 的重塑复合物结合。 BAHCC1 沉默会导致细胞增殖减少和 DNA 修复延迟。因此，BAHCC1 缺陷与 PARP 抑制协同作用，诱导黑色素瘤细胞死亡。我们的研究将 BAHCC1 确定为黑色素瘤中表达的 SE 驱动基因，并展示了如何利用其抑制作用作为治疗靶点。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Super-enhancers (SEs) are stretches of enhancers ensuring a high level of expression of key genes associated with cell function. The identification of cancer-specific SE-driven genes is a powerful means for the development of innovative therapeutic strategies. Here, we identify a MITF/SOX10/TFIIH-dependent SE promoting the expression of BAHCC1 in a broad panel of melanoma cells. BAHCC1 is highly expressed in metastatic melanoma and is required for tumor engraftment, growth, and dissemination. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of E2F/KLF-dependent cell-cycle and DNA-repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. BAHCC1 silencing leads to decreased cell proliferation and delayed DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies BAHCC1 as an SE-driven gene expressed in melanoma and demonstrates how its inhibition can be exploited as a therapeutic target.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.