Original Article

Oncogene advance online publication 3 April 2017; doi: 10.1038/onc.2017.75

There is a Corrigendum (19 June 2017) associated with this article.

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

A Noto1, C De Vitis1, M E Pisanu2, G Roscilli1, G Ricci3, A Catizone4, G Sorrentino5, G Chianese6, O Taglialatela-Scafati6, D Trisciuoglio7, D Del Bufalo7, M Di Martile7, A Di Napoli1, L Ruco1, S Costantini2, Z Jakopin8, A Budillon2, G Melino9, G Del Sal5,10, G Ciliberto2,11 and R Mancini1

  1. 1Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
  2. 2IRCCS, National Cancer Institute, Fondazione ‘G Pascale’, Naples, Italy
  3. 3Department of Experimental Medicine, Università Degli Studi Della Campania ‘Luigi Vanvitelli’, Naples, Italy
  4. 4Section of Histology and Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Faculty of Pharmacy and Medicine, ‘Sapienza’ University of Rome, Rome, Italy
  5. 5Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy
  6. 6Department of Pharmacy, University of Naples Federico II, Naples, Italy
  7. 7Preclinical Models and New Therapeutic Agents Units, Research Advanced Diagnostics and Technological Innovation Department, IRCSS National Cancer Institute ‘Regina Elena’, Rome, Italy
  8. 8Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
  9. 9Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK
  10. 10Department ‘Scienze Della Vita, University of Trieste, Trieste, Italy
  11. 11IRCSS National Cancer Institute ‘Regina Elena’, Rome, Italy

Correspondence: Dr G Ciliberto, IRCSS Istituto Nazionale Tumori ‘Regina Elena’, Via Elio Chianesi 53, Rome 00144, Italy. E-mail: gennaro.ciliberto@ifo.gov.it

Received 29 August 2016; Revised 3 February 2017; Accepted 17 February 2017
Advance online publication 3 April 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.