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Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral comp...

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Detalles Bibliográficos
Autores principales: Afanasyeva, Elena A, Gartlgruber, Moritz, Ryl, Tatsiana, Decaesteker, Bieke, Denecker, Geertrui, Mönke, Gregor, Toprak, Umut H, Florez, Andres, Torkov, Alica, Dreidax, Daniel, Herrmann, Carl, Okonechnikov, Konstantin, Ek, Sara, Sharma, Ashwini Kumar, Sagulenko, Vitaliya, Speleman, Frank, Henrich, Kai-Oliver, Westermann, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017594/
https://www.ncbi.nlm.nih.gov/pubmed/33658318
http://dx.doi.org/10.26508/lsa.201900332
Descripción
Sumario:The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin–GEF1–suppressed ADRN-type cells are a batch of AU-rich element–containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis–based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.