超级增强子驱动 BAHCC1 的表达促进黑色素瘤细胞的增殖和基因组稳定性。

Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability.

机构信息

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Equipe Labéllisée, "Ligue contre le Cancer 2022", BP 163, 67404 Illkirch Cedex, C.U. Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, NYU Langone Health, New York, NY 10016, USA.

出版信息

Cell Rep. 2023 Nov 28;42(11):113363. doi: 10.1016/j.celrep.2023.113363. Epub 2023 Nov 3.

DOI:10.1016/j.celrep.2023.113363

PMID:37924516

Abstract

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.

摘要

超级增强子（SEs）是确保与细胞功能相关的关键基因高水平表达的增强子区域。鉴定癌症特异性 SE 驱动基因是开发创新治疗策略的有力手段。在这里，我们鉴定了一个由 MITF/SOX10/TFIIH 依赖性 SE 驱动的基因，该基因在广泛的黑色素瘤细胞系中促进 BAHCC1 的表达。BAHCC1 在转移性黑色素瘤中高表达，是肿瘤移植、生长和扩散所必需的。综合基因组分析显示，BAHCC1 是一个转录调控因子，控制着 E2F/KLF 依赖性细胞周期和 DNA 修复基因的表达。BAHCC1 与包含 BRG1 的重塑复合物在这些基因的启动子处结合。BAHCC1 的沉默导致细胞增殖减少和 DNA 修复延迟。因此，BAHCC1 缺陷与 PARP 抑制协同诱导黑色素瘤细胞死亡。我们的研究鉴定了 BAHCC1 作为一种在黑色素瘤中表达的 SE 驱动基因，并展示了如何利用其抑制作为治疗靶点。