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Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma

Abstract

Accumulating 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 SQSTM1/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.

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Code to reproduce key parts of the analysis can be obtained upon request from the authors.

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Acknowledgements

This study was supported by the Finnish Cancer Organizations, The Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Academy of Finland, Finnish Cultural Foundation, Cancer Society of Finland, North-Savo Regional Cancer Society and Fund of Matti and Vappu Maukonen. Mrs. Arja Korhonen is thanked for her technical assistance. We thank SIBLabs for performing TEM and Dr. Eeva-Liisa Eskelinen, University of Helsinki, for helping with the analysis of TEM pictures.

Author contributions

Conception and design: PP, MH, and A-LL. Development of methodology: PP, AD, HL, MH, and MN. Acquisition of data: PP, AD, HL, H-KJ, and SK. Analysis and interpretation of data: PP, AD, and HL. Writing, review, and/or revision of the paper: PP, MH, A-LL, AD, and HL. Administrative, technical, or material support: MM, AJ, TT, SP-S, JH, AM, PT, and TJ. Study supervision: A-LL and MH.

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Correspondence to Anna-Liisa Levonen.

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Pölönen, P., Jawahar Deen, A., Leinonen, H.M. et al. Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma. Oncogene 38, 7473–7490 (2019). https://doi.org/10.1038/s41388-019-0956-6

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