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Post-translational inhibition of YAP oncogene expression by 4-hydroxynonenal in bladder cancer cells.

Abstract

The transcriptional regulator YAP plays an important role in cancer progression and is negatively controlled by the Hippo pathway. YAP is frequently overexpressed in human cancers, including bladder cancer. Interestingly, YAP expression and activity can be inhibited by pro-oxidant conditions; moreover, YAP itself can also affect the cellular redox status through multiple mechanisms. 4-Hydroxynonenal (HNE), the most intensively studied end product of lipid peroxidation, is a pro-oxidant agent able to deplete GSH and has an anti-tumoral effect by affecting multiple signal pathways, including the down-regulation of oncogene expressions. These observations prompted us to investigate the effect of HNE on YAP expression and activity. We demonstrated that HNE inhibited YAP expression and its target genes in bladder cancer cells through a redox-dependent mechanism. Moreover, the YAP down-regulation was accompanied by an inhibition of proliferation, migration, invasion, and angiogenesis, as well as by an accumulation of cells in the G2/M phase of cell cycle and by an induction of apoptosis. We also established the YAP role in inhibiting cell viability and inducing apoptosis in HNE-treated cells by using an expression vector for YAP. Furthermore, we identified a post-translational mechanism for the HNE-induced YAP expression inhibition, involving an increase of YAP phosphorylation and ubiquitination, leading to proteasomal degradation. Our data established that HNE can post-translationally down-regulate YAP through a redox-dependent mechanism and that this modulation can contribute to determining the specific anti-cancer effects of HNE.

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  • Authors+Show Affiliations

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    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

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    Department of Oncology, University of Turin, Via Michelangelo 27, 10125, Turin, Italy.

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    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

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    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

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    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

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    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

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    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

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    Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125, Turin, Italy.

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    Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125, Turin, Italy.

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    Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125, Turin, Italy.

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    Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.

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    Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy.

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    Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125, Turin, Italy.

    ,

    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy.

    Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Regione Gonzole 10, 10043, Orbassano, Turin, Italy. Electronic address: stefania.pizzimenti@unito.it.

    Source

    Free radical biology & medicine 141: 2019 Jun 15 pg 205-219

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31207288

    Citation

    Cucci, Marie Angele, et al. "Post-translational Inhibition of YAP Oncogene Expression By 4-hydroxynonenal in Bladder Cancer Cells." Free Radical Biology & Medicine, vol. 141, 2019, pp. 205-219.
    Cucci MA, Compagnone A, Daga M, et al. Post-translational inhibition of YAP oncogene expression by 4-hydroxynonenal in bladder cancer cells. Free Radic Biol Med. 2019;141:205-219.
    Cucci, M. A., Compagnone, A., Daga, M., Grattarola, M., Ullio, C., Roetto, A., ... Pizzimenti, S. (2019). Post-translational inhibition of YAP oncogene expression by 4-hydroxynonenal in bladder cancer cells. Free Radical Biology & Medicine, 141, pp. 205-219. doi:10.1016/j.freeradbiomed.2019.06.009.
    Cucci MA, et al. Post-translational Inhibition of YAP Oncogene Expression By 4-hydroxynonenal in Bladder Cancer Cells. Free Radic Biol Med. 2019 Jun 15;141:205-219. PubMed PMID: 31207288.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Post-translational inhibition of YAP oncogene expression by 4-hydroxynonenal in bladder cancer cells. AU - Cucci,Marie Angele, AU - Compagnone,Alessandra, AU - Daga,Martina, AU - Grattarola,Margherita, AU - Ullio,Chiara, AU - Roetto,Antonella, AU - Palmieri,Antonietta, AU - Rosa,Arianna Carolina, AU - Argenziano,Monica, AU - Cavalli,Roberta, AU - Simile,Maria Maddalena, AU - Pascale,Rosa Maria, AU - Dianzani,Chiara, AU - Barrera,Giuseppina, AU - Pizzimenti,Stefania, Y1 - 2019/06/15/ PY - 2018/12/07/received PY - 2019/03/15/revised PY - 2019/06/07/accepted PY - 2019/6/18/pubmed PY - 2019/6/18/medline PY - 2019/6/18/entrez KW - 4-Hydroxynonenal KW - A375 melanoma cells KW - Angiogenesis KW - Apoptosis KW - CRL2335 breast cancer cells KW - Cell cycle KW - Cell proliferation KW - GSH KW - Hippo signaling pathway KW - Invasion KW - Migration KW - N-acetylcysteine KW - Proteasome KW - T24 bladder cancer cells KW - Transfection KW - Ubiquitination KW - YAP KW - p-YAP ser127 KW - p-YAP ser387 SP - 205 EP - 219 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 141 N2 - The transcriptional regulator YAP plays an important role in cancer progression and is negatively controlled by the Hippo pathway. YAP is frequently overexpressed in human cancers, including bladder cancer. Interestingly, YAP expression and activity can be inhibited by pro-oxidant conditions; moreover, YAP itself can also affect the cellular redox status through multiple mechanisms. 4-Hydroxynonenal (HNE), the most intensively studied end product of lipid peroxidation, is a pro-oxidant agent able to deplete GSH and has an anti-tumoral effect by affecting multiple signal pathways, including the down-regulation of oncogene expressions. These observations prompted us to investigate the effect of HNE on YAP expression and activity. We demonstrated that HNE inhibited YAP expression and its target genes in bladder cancer cells through a redox-dependent mechanism. Moreover, the YAP down-regulation was accompanied by an inhibition of proliferation, migration, invasion, and angiogenesis, as well as by an accumulation of cells in the G2/M phase of cell cycle and by an induction of apoptosis. We also established the YAP role in inhibiting cell viability and inducing apoptosis in HNE-treated cells by using an expression vector for YAP. Furthermore, we identified a post-translational mechanism for the HNE-induced YAP expression inhibition, involving an increase of YAP phosphorylation and ubiquitination, leading to proteasomal degradation. Our data established that HNE can post-translationally down-regulate YAP through a redox-dependent mechanism and that this modulation can contribute to determining the specific anti-cancer effects of HNE. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/31207288/Post-translational_inhibition_of_YAP_oncogene_expression_by_4-hydroxynonenal_in_bladder_cancer_cells L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(18)32523-1 DB - PRIME DP - Unbound Medicine ER -