Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
Department of Microbiology, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea.
Cell Rep. 2018 Jul 3;24(1):224-237. doi: 10.1016/j.celrep.2018.06.020.
Breast cancer cells relocate to bone and activate osteoclast-induced bone resorption. Soluble factors secreted by breast cancer cells trigger a cascade of events that stimulate osteoclast differentiation in the bone microenvironment. MacroH2A is a unique histone variant with a C-terminal non-histone domain and plays a crucial role in modulating chromatin organization and gene transcription. Here, we show that macroH2A1.2, one of the macroH2A isoforms, has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis. This repressive effect requires macroH2A1.2-dependent attenuation of expression and secretion of lysyl oxidase (LOX) in breast cancer cells. Furthermore, our mechanistic studies reveal that macroH2A1.2 physically and functionally interacts with the histone methyltransferase EZH2 and elevates H3K27me3 levels to keep LOX gene in a repressed state. Collectively, this study unravels a role for macroH2A1.2 in regulating osteoclastogenic potential of breast cancer cells, suggesting possibilities for developing therapeutic tools to treat osteolytic bone destruction.
乳腺癌细胞转移到骨骼并激活破骨细胞诱导的骨吸收。乳腺癌细胞分泌的可溶性因子引发一系列事件，刺激骨微环境中破骨细胞的分化。MacroH2A 是一种具有独特的 C 末端非组蛋白结构域的组蛋白变体，在调节染色质组织和基因转录中发挥着关键作用。在这里，我们发现 MacroH2A1.2（MacroH2A 的一种同工型）具有内在的抑制乳腺癌来源的破骨细胞发生的能力。这种抑制作用需要 MacroH2A1.2 依赖性地减弱乳腺癌细胞中赖氨酰氧化酶 (LOX) 的表达和分泌。此外，我们的机制研究表明，MacroH2A1.2 与组蛋白甲基转移酶 EZH2 发生物理和功能相互作用，并增加 H3K27me3 水平，使 LOX 基因处于抑制状态。总的来说，这项研究揭示了 MacroH2A1.2 在调节乳腺癌细胞破骨细胞发生潜能中的作用，为开发治疗溶骨性骨破坏的治疗工具提供了可能性。
