A1 Refereed original research article in a scientific journal
The PP2A regulator IER5L supports prostate cancer progression
Authors: Crespo, Jana R.; Martín-Martín, Natalia; Garcia-Longarte, Saioa; Corres-Mendizabal, Jon; Carlevaris, Onintza; Astobiza, Ianire; Zabala-Letona, Amaia; Guiu, Marc; Azkargorta, Mikel; Gonzalez-Lopez, Monika; Macías-Cámara, Nuria; Doan, Phuong; Elortza, Félix; Mendizabal, Isabel; Westermack, Jukka; Gomis, Roger R.; Ercilla, Amaia; Carracedo, Arkaitz
Publisher: Springer Nature
Publication year: 2024
Journal: Cell Death and Disease
Journal name in source: Cell death & disease
Journal acronym: Cell Death Dis
Article number: 514
Volume: 15
eISSN: 2041-4889
DOI: https://doi.org/10.1038/s41419-024-06907-z
Web address : https://www.nature.com/articles/s41419-024-06907-z
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/457298708
Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology. Here, we show that the less studied member of this family, Immediate Early Response 5 like (IER5L), is upregulated in aggressive prostate cancer. Interestingly, the upregulation of IER5L expression exhibits a robust association with metastatic disease in prostate and is recapitulated in other cancer types. In line with this observation, IER5L silencing reduces foci formation, migration and invasion ability in a variety of human and murine prostate cancer cell lines. In vivo, using zebrafish and immunocompromised mouse models, we demonstrate that IER5L-silencing reduces prostate cancer tumor growth, dissemination, and metastasis. Mechanistically, we characterize the transcriptomic and proteomic landscapes of IER5L-silenced cells. This approach allowed us to identify DNA replication and monomeric G protein regulators as downstream programs of IER5L through a pathway that is consistent with the regulation of PP2A. In sum, we report the alteration of IER5L in prostate cancer and beyond and provide biological and molecular evidence of its contribution to tumor aggressiveness.
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Funding information in the publication:
The work of A. Carracedo is supported by Fundación Cris Contra el Cáncer (PR_EX_2021-22), La Caixa Foundation under the agreement LCF/PR/HR17, the Basque Department of Industry, Tourism and Trade (Elkartek), the BBVA foundation (Becas Leonardo), the MICINN (PID2019-108787RB-I00; PID2022-141553OB-I0 (FEDER/EU); Severo Ochoa Excellence Accreditation CEX2021-001136-S), European Training Networks Project (H2020-MSCA-ITN-308 2016 721532), the AECC (GCTRA18006CARR), Vencer el Cáncer Foundation, the iDIFFER network of Excellence (RED2022-134792-T) and the European Research Council (Consolidator Grant 819242). CIBERONC was co-funded with FEDER funds and funded by ISCIII. AE was supported by a Juan de la Cierva Incorporación fellowship from the MCIN/AEI /10.13039/501100011033 and European Union NextGenerationEU/PRTR. IM is supported by Fundación Cris Contra el Cáncer (PR_TPD_2020-19). RRG and MG were supported by AECC Grant proyecto GCTRA18006CARR; and MICINN and FEDER funds (CIBERONC and PID2019-104948RB-I00; PID2022-143093OB-100). JW is supported by Finnish Cancer Foundations.
