Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China; Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China.
Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt A):1104-1114. doi: 10.1016/j.bbadis.2018.01.011. Epub 2018 Jan 12.
Arg Kinase-binding protein 2 (ArgBP2) is considered to be a scaffold protein that coordinates multiple signaling pathways converging on cell adhesion and actin cytoskeletal organization. It also plays an important role in blocking cancer metastasis as a potential tumor suppressor. However, its regulation mechanisms in tumor migration, especially in gastric cancer, are not fully understood. Here, we identified an ArgBP2 enhancer and showed that heat shock factor 1 (HSF1) directly interacted with microrchidia CW-type zinc finger 2 (MORC2) and bound to the enhancer of ArgBP2. HSF1 was found to promote proliferation, migration and invasion of gastric cancer cells. HSF1 or/and MORC2 increased recruitment of the polycomb repressive complex 2 (PRC2), particularly enhancer of zeste homolog 2 (EZH2), to the ArgBP2 enhancer and catalyzed tri-methylation of lysine 27 on histone H3 (H3K27me3), leading to transcriptional repression of ArgBP2. In addition, HSF1 and MORC2-induced migration and invasion in gastric cancer cells was dependent on ArgBP2 or EZH2. Clinical data exhibited a negative correlation of ArgBP2 with MORC2, HSF1, and EZH2. Our results thus contribute to the knowledge of the regulatory mechanism of HSF1 in down-regulating ArgBP2, providing new insight into the HSF1&MORC2-PRC2-ArgBP2 signaling pathway and a better understanding of their functions in gastric cancer cells.
Arg 激酶结合蛋白 2（ArgBP2）被认为是一种支架蛋白，可协调多个信号通路，汇聚于细胞黏附和肌动蛋白细胞骨架组织。它作为一种潜在的肿瘤抑制因子，在阻断癌症转移方面也起着重要作用。然而，其在肿瘤迁移中的调控机制，特别是在胃癌中的调控机制，尚未完全阐明。在这里，我们鉴定了 ArgBP2 的增强子，并表明热休克因子 1（HSF1）直接与微线体 CW 型锌指 2（MORC2）相互作用，并与 ArgBP2 的增强子结合。发现 HSF1 可促进胃癌细胞的增殖、迁移和侵袭。HSF1 或/和 MORC2 增加多梳抑制复合物 2（PRC2），特别是增强子的 zeste 同源物 2（EZH2），募集到 ArgBP2 增强子，并催化组蛋白 H3 赖氨酸 27 的三甲基化（H3K27me3），导致 ArgBP2 的转录抑制。此外，HSF1 和 MORC2 诱导胃癌细胞的迁移和侵袭依赖于 ArgBP2 或 EZH2。临床数据显示 ArgBP2 与 MORC2、HSF1 和 EZH2 呈负相关。因此，我们的研究结果为 HSF1 下调 ArgBP2 的调控机制提供了新的见解，为 HSF1&MORC2-PRC2-ArgBP2 信号通路提供了新的认识，并加深了对其在胃癌细胞中功能的理解。
