Vardabasso Chiara, Gaspar-Maia Alexandre, Hasson Dan, Pünzeler Sebastian, Valle-Garcia David, Straub Tobias, Keilhauer Eva C, Strub Thomas, Dong Joanna, Panda Taniya, Chung Chi-Yeh, Yao Jonathan L, Singh Rajendra, Segura Miguel F, Fontanals-Cirera Barbara, Verma Amit, Mann Matthias, Hernando Eva, Hake Sandra B, Bernstein Emily
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Mol Cell. 2015 Jul 2;59(1):75-88. doi: 10.1016/j.molcel.2015.05.009. Epub 2015 Jun 4.
Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.
组蛋白变体正逐渐成为癌症中的关键调控分子。我们报告了H2A.Z亚型H2A.Z.2作为恶性黑色素瘤驱动因子的独特作用。H2A.Z.2在转移性黑色素瘤中高表达，与患者生存率降低相关，且是细胞增殖所必需的。我们的综合基因组分析表明，H2A.Z.2控制黑色素瘤细胞中E2F靶基因的转录输出。这些基因高度表达，并呈现出H2A.Z占据的独特特征。我们鉴定出BRD2是一种与H2A.Z相互作用的蛋白，其在黑色素瘤中的水平也升高。我们进一步证明，H2A.Z.2调控的基因以H2A.Z.2依赖的方式被BRD2和E2F1结合。重要的是，H2A.Z.2缺陷使黑色素瘤细胞对化疗和靶向治疗敏感。总的来说，我们的研究结果表明H2A.Z.2是恶性黑色素瘤细胞增殖和药物敏感性的介质，具有新治疗策略的转化潜力。
