Disease-specific alteration of karyopherin-[alpha] subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

Nuclear import, mediated in part by karyopherin-[alpha] (KPNA)/importin-[alpha] 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 th...

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Bibliographic Details
Published in:Oncogene 2020-03, Vol.39 (10), p.2212
Main Authors: Hazawa, Masaharu, Sakai, Kie, Kobayashi, Akiko, Yoshino, Hironori, Iga, Yoshihiro, Iwashima, Yuki, Lim, Kee Sing
Format: Article
Language:English
Subjects:
Care and treatment
Carrier proteins
Cellular signal transduction
Development and progression
Genetic aspects
Head and neck cancer
Health aspects
Squamous cell carcinoma
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Summary:Nuclear import, mediated in part by karyopherin-[alpha] (KPNA)/importin-[alpha] 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]4 (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.
ISSN:0950-9232
DOI:10.1038/s41388-019-1137-3