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.

Stearoyl-CoA desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ / Noto, A.; De Vitis, C.; Pisanu, M. E.; Roscilli, G.; Ricci, G.; Catizone, A.; Sorrentino, G.; Chianese, Giuseppina; TAGLIALATELA SCAFATI, Orazio; Triscuoglio, D.; Del Bufalo, D.; Di Martile, M.; Di Napoli, A.; Ruco, L.; Costantini, S.; Jakopin, Z.; Budillon, A.; Melino, G.; Del Sal, G.; Ciliberto, G.; Mancini, R.. - In: ONCOGENE. - ISSN 1476-5594. - 36:(2017), pp. 4573-4584. [10.1038/onc.2017.75]

Stearoyl-CoA desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ

CHIANESE, GIUSEPPINA
Membro del Collaboration Group
;
TAGLIALATELA SCAFATI, ORAZIO;
2017

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.
2017
Stearoyl-CoA desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ / Noto, A.; De Vitis, C.; Pisanu, M. E.; Roscilli, G.; Ricci, G.; Catizone, A.; Sorrentino, G.; Chianese, Giuseppina; TAGLIALATELA SCAFATI, Orazio; Triscuoglio, D.; Del Bufalo, D.; Di Martile, M.; Di Napoli, A.; Ruco, L.; Costantini, S.; Jakopin, Z.; Budillon, A.; Melino, G.; Del Sal, G.; Ciliberto, G.; Mancini, R.. - In: ONCOGENE. - ISSN 1476-5594. - 36:(2017), pp. 4573-4584. [10.1038/onc.2017.75]
File in questo prodotto:
File Dimensione Formato  
Noto_etal_2017.pdf

non disponibili

Descrizione: Articolo principale
Tipologia: Versione Editoriale (PDF)
Licenza: Accesso privato/ristretto
Dimensione 3.72 MB
Formato Adobe PDF
3.72 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/679818
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 128
  • ???jsp.display-item.citation.isi??? 120
social impact