Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma.

Nuclear import, mediated in part by karyopherin-α subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that encoding karyopherin-α4 is exclusively amplified and overexpressed in head and neck of squamous cell carcinoma (HNSCC). Depletion of attenuated nuclear localization signal-dependent transport activity and suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, 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 Kduanyu15354 via phosphorylation of Kduanyu15354 at Ser60. These data reveal that Kduanyu15354 establishes a feed-forward cascade that potentiates Ras/ERK signaling in HNSCC.

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