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      Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models

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          Abstract

          The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.

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          The RSK family of kinases: emerging roles in cellular signalling.

          The 90 kDa ribosomal S6 kinase (RSK) family of proteins is a group of highly conserved Ser/Thr kinases that regulate diverse cellular processes, such as cell growth, cell motility, cell survival and cell proliferation. RSKs are downstream effectors of the Ras-extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling cascade. Significant advances in the field of RSK and ERK/MAPK signalling have occurred in the past few years, including biological insights and the discovery of novel substrates and new RSK regulatory mechanisms. Collectively, these data expand the current models of RSK signalling and highlight potential directions of research in RSK-mediated survival, growth, proliferation and migration.
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            Y-box-binding protein 1 (YB-1) and its functions.

            This review describes the structure and functions of Y-box binding protein 1 (YB-1) and its homologs. Interactions of YB-1 with DNA, mRNAs, and proteins are considered. Data on the participation of YB-1 in DNA reparation and transcription, mRNA splicing and translation are systematized. Results on interactions of YB-1 with cytoskeleton components and its possible role in mRNA localization are discussed. Data on intracellular distribution of YB-1, its redistribution between the nucleus and the cytoplasm, and its secretion and extracellular functions are summarized. The effect of YB-1 on cell differentiation, its involvement in extra- and intracellular signaling pathways, and its role in early embryogenesis are described. The mechanisms of regulation of YB-1 expression in the cell are presented. Special attention is paid to the involvement of YB-1 in oncogenic cell transformation, multiple drug resistance, and dissemination of tumors. Both the oncogenic and antioncogenic activities of YB-1 are reviewed. The potential use of YB-1 in diagnostics and therapy as an early cancer marker and a molecular target is discussed.
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              Regulation and function of the RSK family of protein kinases.

              The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine kinases that regulate diverse cellular processes, including cell growth, proliferation, survival and motility. This family includes four vertebrate isoforms (RSK1, RSK2, RSK3 and RSK4), and single family member orthologues are also present in Drosophila and Caenorhabditis elegans. The RSK isoforms are downstream effectors of the Ras/ERK (extracellular-signal-regulated kinase) signalling pathway. Significant advances in the field of RSK signalling have occurred in the past few years, including several new functions ascribed to the RSK isoforms, the discovery of novel protein substrates and the implication of different RSK isoforms in cancer. Collectively, these new findings increase the diversity of biological functions regulated by RSK, and highlight potential new directions of research. In the present paper, we review the structure, expression and activation mechanisms of the RSK isoforms, and discuss their physiological roles on the basis of established substrates and recent discoveries.
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                Author and article information

                Contributors
                dsyed@dermatology.wisc.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 October 2018
                24 October 2018
                2018
                : 8
                : 15726
                Affiliations
                [1 ]ISNI 0000 0001 0701 8607, GRID grid.28803.31, Department of Dermatology, , University of Wisconsin, ; Madison, USA
                [2 ]ISNI 0000 0001 0701 8607, GRID grid.28803.31, Department of Neuroscience, , University of Wisconsin, ; Madison, USA
                [3 ]ISNI 0000 0001 2097 9138, GRID grid.11450.31, Department of Chemistry and Pharmacy, , University of Sassari, ; Sassari, Italy
                Article
                33879
                10.1038/s41598-018-33879-w
                6200766
                30356079
                a8013059-6408-41d3-bdea-5a1954d772e6
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 14 November 2017
                : 6 October 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003852, Regione Campania;
                Award ID: CRP-25920
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: P30AR066524
                Award ID: P30AR066524
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000069, U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS);
                Award ID: AR059742
                Award ID: R21AR067466
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000066, U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS);
                Award ID: AR059742
                Award Recipient :
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