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Knockdown of NUP62 of human head and neck squamous cell carcinoma cell line UMSCC1

ABSTRACT: p63, especially its dominant isoform ∆Np63⍺, plays essential roles in squamous cell carcinomas (SCCs); yet the mechanisms controlling its nuclear transport remain unknown. Nucleoporins (NUPs) are a family of proteins building nuclear pore complex (NPC) and mediating nuclear transport across the nuclear envelope. Recent evidence suggests a cell-type-specific function for certain NUPs; however, the significance of NUPs in SCC biology remains unknown. In this study, we report that nucleoporin 62 (NUP62) is highly expressed in stratified squamous epithelia, which is further elevated in SCCs. Depletion of NUP62 inhibited the proliferation ability and augmented differentiation characteristics of SCC cells. This loss of dedifferentiation status was associated with defects in ∆Np63⍺ nuclear transport. We further found that differentiation inducible Rho kinase reduced an interaction between NUP62 and ∆Np63a by phosphorylation of phenylalanine-glycine regions of NUP62, resulting in attenuated ∆Np63⍺ nuclear import. Our results characterize NUP62 as a key gatekeeper for ∆Np63⍺ and uncover its significant function to control ∆Np63⍺ nuclear transport in SCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103991 | GEO | 2017/11/16

SECONDARY ACCESSION(S): PRJNA407901

REPOSITORIES: GEO

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Nucleoporin Nup153 Regulates Stem Cell Pluripotency through Gene Silencing

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Project description:The oncoprotein ∆Np63 is an essential transcriptional master- and cell identity regulator in squamous cell carcinoma (SCC) of various origins, encompassing lung, head and neck, oesophagus, cervix and skin. While in non-transformed cells ∆Np63 protein abundance is tightly regulated by the ubiquitin proteasome system (UPS), in tumours E3-ligases ubiquitylating ∆Np63, such as FBXW7, are commonly mutated or lost, resulting in a hyper-stabilisation of the oncogenic driver. Targeting ∆Np63 protein abundance in SCC could present a possible therapeutic avenue. Here, we report that the deubiquitylase USP28 regulates ∆Np63 protein stability and abundance in SCC by counteracting the degradative UPS system. Interference with USP28 activity by pharmacological inhibition specifically affected human SCC cell lines and, finally, we were able to demonstrate in vivo using CRISPR/Cas9 mouse models that Usp28 is required for SCC induction and maintenance. Hence, targeting USP28 is a viable option to tackle ∆Np63 protein abundance in SCC tumours.

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