ABSTRACT
This corrects the article DOI: 10.1038/onc.2017.75.
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 ß-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 ß-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 ß-catenin and YAP/TAZ. Mining available gene expression data sets allowed to observe that high co-expression levels of SCD1, ß-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, ß-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.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Adenocarcinoma/metabolism , Cell Nucleus/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/metabolism , Neoplastic Stem Cells/metabolism , Phosphoproteins/metabolism , Stearoyl-CoA Desaturase/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Axin Signaling Complex/metabolism , Down-Regulation , Fatty Acids/metabolism , Female , HEK293 Cells , Hippo Signaling Pathway , Humans , Immunohistochemistry , Inhibitor of Apoptosis Proteins/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Neoplasm Proteins/metabolism , Primary Cell Culture , Prognosis , Protein Serine-Threonine Kinases/metabolism , Protein Stability , RNA, Messenger/metabolism , Stearoyl-CoA Desaturase/antagonists & inhibitors , Stearoyl-CoA Desaturase/genetics , Survivin , Trans-Activators , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , Wnt3A Protein/metabolism , YAP-Signaling ProteinsABSTRACT
The saccharin ring system has gained considerable attention in the past decades, especially in the field of medicinal chemistry. The wide applicability of saccharin derivatives remains the driving force behind the constant development of novel routes and methods that provide new access to the construction of saccharin. Since the functionalization of this heterocycle has proved difficult, except for N- and O-alkylation, novel strategic approaches are much sought-after and thus constitute a great value to any medicinal chemist. In addition to the synthetic novelties introduced into the synthesis and functionalization of this particular heterocycle, the numerous newly discovered biological activities of saccharin and its derivatives are also reviewed. Saccharin may be considered to constitute a privileged framework on account of its role as a key structural element in several biologically active compounds ranging from enzyme inhibitors to receptor ligands and beyond.
