Disease-specific alteration of karyopherin-alpha 4 subtype establishes feed-forward oncogenic signaling in squamous cell carcinoma

Nuclear import, mediated in part by karyopherin-alpha 4 (KPNA) 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-alpha 44 (KPNA4), is exclusively amplified and overexpressed in various forms of squamous cell carcinomas (SCCs). Depletion of KPNA4 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 SCCs. Comaprison between negative control cells and KPNA4 knocked down cells. There are two biological replicates for each conditions.