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

A. Noto, C De Vitis, Maria Elena Pisanu, Giuseppe Roscilli, G Ricci, Angela Catizone, G Sorrentino, Giuseppe Chianese, Orazio Taglialatela-Scafati, D Trisciuoglio, D Del Bufalo, Marta Di Martile, A. Napoli, Luigi Ruco, S Costantini, Z Jakopin, A Budillon, G Melino, Giannino Del Sal, G Ciliberto & 1 others R. Mancini

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

Original languageEnglish
JournalOncogene
DOIs
Publication statusPublished - Aug 2017

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Stearoyl-CoA Desaturase
Lung Neoplasms
Catenins
Proteins
Neoplastic Stem Cells
Monounsaturated Fatty Acids
Primary Cell Culture
Computational Biology
Oncogenes
Publications
Cell Survival
Fatty Acids
Down-Regulation
Immunohistochemistry

Keywords

  • Journal Article

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Noto, A., De Vitis, C., Pisanu, M. E., Roscilli, G., Ricci, G., Catizone, A., ... Mancini, R. (2017). Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. Oncogene. https://doi.org/10.1038/onc.2017.75

Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. / Noto, A.; De Vitis, C; Pisanu, Maria Elena; Roscilli, Giuseppe; Ricci, G; Catizone, Angela; Sorrentino, G; Chianese, Giuseppe; Taglialatela-Scafati, Orazio; Trisciuoglio, D; Del Bufalo, D; Di Martile, Marta; Napoli, A.; Ruco, Luigi; Costantini, S; Jakopin, Z; Budillon, A; Melino, G; Del Sal, Giannino; Ciliberto, G; Mancini, R.

In: Oncogene, 08.2017.

Research output: Contribution to journalArticle

Noto, A, De Vitis, C, Pisanu, ME, Roscilli, G, Ricci, G, Catizone, A, Sorrentino, G, Chianese, G, Taglialatela-Scafati, O, Trisciuoglio, D, Del Bufalo, D, Di Martile, M, Napoli, A, Ruco, L, Costantini, S, Jakopin, Z, Budillon, A, Melino, G, Del Sal, G, Ciliberto, G & Mancini, R 2017, 'Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ', Oncogene. https://doi.org/10.1038/onc.2017.75
Noto, A. ; De Vitis, C ; Pisanu, Maria Elena ; Roscilli, Giuseppe ; Ricci, G ; Catizone, Angela ; Sorrentino, G ; Chianese, Giuseppe ; Taglialatela-Scafati, Orazio ; Trisciuoglio, D ; Del Bufalo, D ; Di Martile, Marta ; Napoli, A. ; Ruco, Luigi ; Costantini, S ; Jakopin, Z ; Budillon, A ; Melino, G ; Del Sal, Giannino ; Ciliberto, G ; Mancini, R. / Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. In: Oncogene. 2017.
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AU - De Vitis, C

AU - Pisanu, Maria Elena

AU - Roscilli, Giuseppe

AU - Ricci, G

AU - Catizone, Angela

AU - Sorrentino, G

AU - Chianese, Giuseppe

AU - Taglialatela-Scafati, Orazio

AU - Trisciuoglio, D

AU - Del Bufalo, D

AU - Di Martile, Marta

AU - Napoli, A.

AU - Ruco, Luigi

AU - Costantini, S

AU - Jakopin, Z

AU - Budillon, A

AU - Melino, G

AU - Del Sal, Giannino

AU - Ciliberto, G

AU - Mancini, R.

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N2 - 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.Oncogene advance online publication, 3 April 2017; doi:10.1038/onc.2017.75.

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

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