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

Abstract

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.

Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex

“…HEK293T cells were propagated in Dulbecco's Modified Eagle's Medium (Wako, 043–30085) supplemented with 10% (v:v) fetal bovine serum (Life Technologies, 10082147) and 50 U/mL penicillin-streptomycin (Nacalai Tesque, 26253–84), as previously described [ 25 ]. Cells were cultured at 37 °C and 5% CO 2 .…”

“…Nuclear/cytoplasmic fractionation analysis was performed using nuclear and cytoplasmic extraction reagents according to the manufacturer's protocol (Thermo Scientific, 78840), as previously described [ 25 , 27 ]. Cytoplasmic and nuclear extracts were then subjected to immunoblotting analysis.…”

Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines

“…Many reports, including the present study, have demonstrated an involvement of nuclear transport receptors in the progression of cancer, making them promising targets for the treatment of cancer [16,30]. Since radiation-chemotherapy is the standard approach for HNSCC treatment, it is extremely important to know whether the blockage of nuclear transport receptors has a therapeutic benefit in that axis.…”

“…There are seven subtypes in the human KPNA family, and each individual KPNA is cargo-specific [15]. Recently, we reported KPNA4 as a HNSCC specifically amplified KPNA, which establishes mitogen-activated protein kinase activation through Ras-responsive element-binding protein 1-nuclear import [16]. Further, the high expression level of KPNA2 is involved in the progression of human breast tumor or human hepatocellular carcinoma [17,18].…”

African Swine Fever Virus MGF360-12L Inhibits Type I Interferon Production by Blocking the Interaction of Importin α and NF-κB Signaling Pathway

“…NF-κB nuclear translocation is not only related to IκBα degradation, but also relevant to interaction with Karyopherins. Karyopherins including karyopherin-α (KPNA) and karyopherin-β (KPNB) is a nuclear transport receptor that is responsible for transporting its specific cargo proteins, which harbor nuclear localization signals (NLSs) through the nuclear pore complex (NPCs) (Beaudet et al 2020 ; Hazawa et al 2020 ). Some viruses, such as Japanese encephalitis virus (JEV) (Ye et al 2017 ), Ebola virus (EBOV) (Reid et al 2006 ), pelargonium line pattern virus (Perez-Canamas and Hernandez 2018 ), hantavirus (HTNV) (Taylor et al 2009 ), prevent nuclear import of cellular cargo molecules by binding importin family proteins or down-regulating importin alpha expression.…”