Biomedical science and engineering interdisciplinary program, KAIST, Daejeon, South Korea.
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Sci Rep. 2016 Sep 6;6:32770. doi: 10.1038/srep32770.
Aberrant Wnt/β-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/β-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/β-catenin signalling in NSCLC cells. KIF3A knockdown increases both β-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds β-arrestin, KIF3A depletion allows β-arrestin to form a complex with DVL2 and axin, stabilizing β-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase β-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as β-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/β-catenin signalling and tumourigenesis in NSCLC.
异常的 Wnt/β-catenin 信号通路与多种人类癌症的进展有关，包括非小细胞肺癌（NSCLC）。然而，Wnt/β-catenin 通路成分的突变在 NSCLC 中并不常见，其表观遗传控制仍不清楚。在这里，我们表明，驱动蛋白-2 家族的成员 KIF3A 在抑制 NSCLC 细胞中的 Wnt/β-catenin 信号通路中发挥作用。KIF3A 敲低会增加 β-连环蛋白的水平和转录活性，并伴随促进恶性潜能，如增加增殖和迁移以及上调干性标志物。因为 KIF3A 与β-抑制蛋白结合，所以 KIF3A 耗尽允许β-抑制蛋白与 DVL2 和轴蛋白形成复合物，稳定 β-连环蛋白。尽管初级纤毛的生物发生需要 KIF3A，但认为其可以抑制 Wnt 反应，但 NSCLC 细胞中纤毛发生的药理学抑制未能增加 β-连环蛋白的活性。KIF3A 缺失与 NSCLC 预后较差以及β-连环蛋白和细胞周期蛋白 D1 上调之间的相关性进一步表明，KIF3A 抑制 NSCLC 中的 Wnt/β-catenin 信号通路和肿瘤发生。
