Department of Pathology, Pathobiology Graduate Program, Oncology Center, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Cancer Res. 2012 Aug 15;72(16):4085-96. doi: 10.1158/0008-5472.CAN-12-0302. Epub 2012 Jul 3.
NAC1 is a transcriptional corepressor protein that is essential to sustain cancer cell proliferation and migration. However, the underlying molecular mechanisms of NAC1 function in cancer cells remain unknown. In this study, we show that NAC1 functions as an actin monomer-binding protein. The conserved BTB protein interaction domain in NAC1 is the minimal region for actin binding. Disrupting NAC1 complex function by dominant-negative or siRNA strategies reduced cell retraction and abscission during late-stage cytokinesis, causing multinucleation in cancer cells. In Nac1-deficient murine fibroblasts, restoring NAC1 expression was sufficient to partially avert multinucleation. We found that siRNA-mediated silencing of the actin-binding protein profilin-1 in cancer cells caused a similar multinucleation phenotype and that NAC1 modulated the binding of actin to profillin-1. Taken together, our results indicate that the NAC1/actin/profilin-1 complex is crucial for cancer cell cytokinesis, with a variety of important biologic and clinical implications.
NAC1 是一种转录核心抑制蛋白，对于维持癌细胞的增殖和迁移至关重要。然而，NAC1 在癌细胞中的功能的潜在分子机制尚不清楚。在这项研究中，我们表明 NAC1 作为肌动蛋白单体结合蛋白发挥作用。NAC1 中的保守 BTB 蛋白相互作用域是肌动蛋白结合的最小区域。通过显性负性或 siRNA 策略破坏 NAC1 复合物功能会减少细胞在末期胞质分裂过程中的回缩和分离，导致癌细胞多核化。在 Nac1 缺陷型小鼠成纤维细胞中，恢复 NAC1 的表达足以部分避免多核化。我们发现，siRNA 介导的对肌动蛋白结合蛋白 Profilin-1 的沉默会导致类似的多核化表型，并且 NAC1 调节肌动蛋白与 Profilin-1 的结合。总之，我们的结果表明，NAC1/肌动蛋白/Profilin-1 复合物对于癌细胞的胞质分裂至关重要，具有多种重要的生物学和临床意义。
