title: Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ.
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.
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Noto
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: De Vitis
authors.affiliation: IRCCS, National Cancer Institute, Fondazione 'G Pascale', Naples, Italy.
authors.forename: M E
authors.initials: ME
authors.lastname: Pisanu
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Roscilli
authors.affiliation: Department of Experimental Medicine, Università Degli Studi Della Campania 'Luigi Vanvitelli', Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ricci
authors.affiliation: Section of Histology and Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Faculty of Pharmacy and Medicine, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Catizone
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sorrentino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Chianese
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: Preclinical Models and New Therapeutic Agents Units, Research Advanced Diagnostics and Technological Innovation Department, IRCSS National Cancer Institute 'Regina Elena', Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Trisciuoglio
authors.affiliation: Preclinical Models and New Therapeutic Agents Units, Research Advanced Diagnostics and Technological Innovation Department, IRCSS National Cancer Institute 'Regina Elena', Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Del Bufalo
authors.affiliation: Preclinical Models and New Therapeutic Agents Units, Research Advanced Diagnostics and Technological Innovation Department, IRCSS National Cancer Institute 'Regina Elena', Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Martile
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Napoli
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ruco
authors.affiliation: IRCCS, National Cancer Institute, Fondazione 'G Pascale', Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Costantini
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Z
authors.initials: Z
authors.lastname: Jakopin
authors.affiliation: IRCCS, National Cancer Institute, Fondazione 'G Pascale', Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Budillon
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy.|Department 'Scienze Della Vita, University of Trieste, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Del Sal
authors.affiliation: IRCCS, National Cancer Institute, Fondazione 'G Pascale', Naples, Italy.|IRCSS National Cancer Institute 'Regina Elena', Rome, Italy.
authors.forename: G
authors.identifier: 0000-0003-2851-8605
authors.initials: G
authors.lastname: Ciliberto
authors.affiliation: Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Mancini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D060465:Axin Signaling Complex / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D061251:Primary Cell Culture; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability; D012333:RNA, Messenger / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D060509:Wnt3A Protein / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060465:Axin Signaling Complex; C107489:BIRC5 protein, human; D005227:Fatty Acids; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D000077022:Survivin; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C555510:WNT3A protein, human; C551991:WWTR1 protein, human; D060509:Wnt3A Protein; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D017346:Protein Serine-Threonine Kinases