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Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ

Oncogene volume 36, pages 4573–4584 (2017)Cite this article

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A Corrigendum to this article was published on 19 June 2017

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Abstract

Recent evidences suggest that stearoyl-CoA-desaturase 1 (SCD1), the enzyme involved in monounsaturated fatty acids synthesis, has a role in several cancers. We previously demonstrated that SCD1 is important in lung cancer stem cells survival and propagation. In this article, we first show, using primary cell cultures from human lung adenocarcinoma, that the effectors of the Hippo pathway, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are required for the generation of lung cancer three-dimensional cultures and that SCD1 knock down and pharmacological inhibition both decrease expression, nuclear localization and transcriptional activity of YAP and TAZ. Regulation of YAP/TAZ by SCD1 is at least in part dependent upon β-catenin pathway activity, as YAP/TAZ downregulation induced by SCD1 blockade can be rescued by the addition of exogenous wnt3a ligand. In addition, SCD1 activation of nuclear YAP/TAZ requires inactivation of the β-catenin destruction complex. In line with the in vitro findings, immunohistochemistry analysis of lung adenocarcinoma samples showed that expression levels of SCD1 co-vary with those of β-catenin and YAP/TAZ. Mining available gene expression data sets allowed to observe that high co-expression levels of SCD1, β-catenin, YAP/TAZ and downstream targets have a strong negative prognostic value in lung adenocarcinoma. Finally, bioinformatics analyses directed to identify which gene combinations had synergistic effects on clinical outcome in lung cancer showed that poor survival is associated with high co-expression of SCD1, β-catenin and the YAP/TAZ downstream target birc5. In summary, our data demonstrate for the first time the involvement of SCD1 in the regulation of the Hippo pathway in lung cancer, and point to fatty acids metabolism as a key regulator of lung cancer stem cells.

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  • 10 August 2017

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

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Acknowledgements

The work was supported by Italian Association for Cancer Research (AIRC) grant IG17009 to RM, and grant IG15216 to GC. Fondo di Ricerca di Ateneo 2014 (C26A142LZ8) and by POR FESR Lazio 2007/2013 to RM. We are grateful to Stefano Piccolo for kindly providing TOP-FLASH reporter plasmid. We acknowledge Claudia Cippittelli for technical support on immunohistochemistry. We acknowledge Italian Association for Cancer Research (AIRC) Special Program Molecular Clinical Oncology ‘5 per mille’ (grant no. 10016), AIRC IG (grant no.17659) and the Italian Ministry of Health (RF-2011-02346976), to GDS.

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Authors and Affiliations

  1. Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy

    A Noto, C De Vitis, G Roscilli, A Di Napoli, L Ruco & R Mancini

  2. IRCCS, National Cancer Institute, Fondazione ‘G Pascale’, Naples, Italy

    M E Pisanu, S Costantini, A Budillon & G Ciliberto

  3. Department of Experimental Medicine, Università Degli Studi Della Campania ‘Luigi Vanvitelli’, Naples, Italy

    G Ricci

  4. Department of Anatomy, Section of Histology and Embryology, Histology, Forensic Medicine and Orthopedics, Faculty of Pharmacy and Medicine, ‘Sapienza’ University of Rome, Rome, Italy

    A Catizone

  5. Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy

    G Sorrentino & G Del Sal

  6. Department of Pharmacy, University of Naples Federico II, Naples, Italy

    G Chianese & O Taglialatela-Scafati

  7. Research Advanced Diagnostics and Technological Innovation Department, Preclinical Models and New Therapeutic Agents Units, IRCSS National Cancer Institute ‘Regina Elena’, Rome, Italy

    D Trisciuoglio, D Del Bufalo & M Di Martile

  8. Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

    Z Jakopin

  9. Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK

    G Melino

  10. Department ‘Scienze Della Vita, University of Trieste, Trieste, Italy

    G Del Sal

  11. IRCSS National Cancer Institute ‘Regina Elena’, Rome, Italy

    G Ciliberto

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Correspondence to G Ciliberto.

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Noto, A., De Vitis, C., Pisanu, M. et al. Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. Oncogene 36, 4573–4584 (2017). https://doi.org/10.1038/onc.2017.75

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