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dc.contributor.authorPölonen, Petri
dc.contributor.authorJawahar Deen, Ashik
dc.contributor.authorLeinonen, Hanna M.
dc.contributor.authorJyrkkänen, Henna-Kaisa
dc.contributor.authorKuosmanen, Suvi
dc.contributor.authorMononen, Mimmi
dc.contributor.authorJain, Ashish
dc.contributor.authorTuomainen, Tomi
dc.contributor.authorPasonen-Seppänen, Sanna
dc.contributor.authorHartikainen, Jaana M.
dc.contributor.authorMannermaa, Arto
dc.contributor.authorNykter, Matti
dc.contributor.authorTavi, Pasi
dc.contributor.authorJohansen, Terje
dc.contributor.authorHeinäniemi, Merja
dc.contributor.authorLevonen, Anna-Liisa
dc.date.accessioned2020-03-18T08:15:11Z
dc.date.available2020-03-18T08:15:11Z
dc.date.issued2019-08-23
dc.description.abstractAccumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote cancer cell proliferation and chemoresistance. The mechanisms of Nrf2 dysregulation and functions in cancer have not been fully characterized. Here, we jointly analyzed the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Atlas (TCGA) multi-omics data in order to identify cancer types where Nrf2 activation is present. We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype, and uncover several different mechanisms contributing to increased Nrf2 activity. Importantly, we identified a positive feedback loop between <i>SQSTM1</i>/p62 and Nrf2 as a mechanism for activation of the Nrf2 pathway. We also show that autophagy and serine/threonine signaling regulates p62 mediated Keap1 degradation. Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition. Finally, Nrf2 activity was associated with decreased progression free survival in TCGA GBM patient samples, suggesting that treatments have limited efficacy if this transcription factor is overactivated. Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance. Thus, Nrf2 activation could be used as a surrogate prognostic marker in mesenchymal subtype GBMs. Furthermore, strategies aiming at either inhibiting Nrf2 or exploiting Nrf2 hyperactivity for targeted gene therapy may provide novel treatment options for this subset of GBM.en_US
dc.identifier.citationPölonen, Jawahar Deen, Leinonen, Jyrkkänen, Kuosmanen, Mononen, Jain Ashish Jain, Tuomainen, Pasonen-Seppänen, Hartikainen JM, Mannermaa A, Nykter M, Tavi P, Johansen T, Heinäniemi, Levonen A. Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma. Oncogene. 2019:1-18en_US
dc.identifier.cristinIDFRIDAID 1739197
dc.identifier.doi10.1038/s41388-019-0956-6
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.urihttps://hdl.handle.net/10037/17781
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.relation.journalOncogene
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright © 2019, Springer Natureen_US
dc.subjectVDP::Medical disciplines: 700en_US
dc.subjectVDP::Medisinske Fag: 700en_US
dc.titleNrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastomaen_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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