期刊
ONCOGENE
卷 39, 期 10, 页码 2212-2223出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-019-1137-3
关键词
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资金
- Infiniti Grant
- Japan Society for Promotion of Science [17K16332, 17H05874, 17K08655]
- Ichiro Kanehara Foundation
- Hokuriku bank young investigator foundation
- Grants-in-Aid for Scientific Research [17K16332, 17K08655, 17H05874] Funding Source: KAKEN
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.
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