Nuclear import, mediated in part by karyopherin-α (KPNA)/importin-α subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of KPNA subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that KPNA4, encoding karyopherin-α4 (KPNA4), is exclusively amplified and overexpressed in head and neck of squamous cell carcinoma (HNSCC). Depletion of KPNA4 attenuated nuclear localization signal-dependent transport activity and suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, KPNA4-mediated nuclear transport of Ras-responsive element-binding protein (RREB1), which sustains Ras/ERK pathway signaling through repressing miR-143/145 expression. Notably, MAPK signaling enhanced trafficking activity of KPNA4 via phosphorylation of KPNA4 at Ser60. These data reveal that KPNA4 establishes a feed-forward cascade that potentiates Ras/ERK signaling in HNSCC.

核输入部分由核转运蛋白-α (KPNA)/输入蛋白-α 亚型介导，调节转录因子进入基因组并决定细胞命运。然而，KPNA 亚型的癌症特异性变化和癌症生物学的相关性仍然很大程度上未知。在这里，我们报告KPNA4，编码 karyopherin-α4 (KPNA4)，仅在鳞状细胞癌 (HNSCC) 的头颈部中扩增和过表达。KPNA4 的消耗减弱了核定位信号依赖的转运活性，抑制了恶性表型并诱导了表皮分化。从机制上讲，KPNA4 介导的 Ras 反应元件结合蛋白 (RREB1) 的核转运，通过抑制 miR-143/145 的表达来维持 Ras/ERK 通路信号传导。值得注意的是，MAPK 信号通过 KPNA4 在 Ser60 的磷酸化增强了 KPNA4 的运输活性。这些数据表明，KPNA4 建立了一个前馈级联，增强了 HNSCC 中的 Ras/ERK 信号传导。