Abstract 1052: Stearoyl-CoA-Desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ
Authors: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Giovanni Sorrentino, Giannino Del Sal, Alfredo Budillon, Gennaro Ciliberto, Rita Mancini
Journal: Cancer Research (2016)

Abstract One of the most common traits of cancer is the radical change of cellular metabolism. A distinctive aspect of this altered metabolic status is the presence of a larger pool of monounsaturated fatty acids (MUFA), the precursors of the components of cell membranes necessary to sustained the rapidly dividing cancer cells. MUFA are largely generated from saturated fatty acids by the action of the two Stearoyl-CoA desaturases isoforms, namely SCD1 and SCD5. Recent evidences suggest that the major isoform SCD1 plays a role in several cancers. Our group has previously reported, using primary adenocarcinoma cell lines from malignant pleural effusions, that SCD1 inhibition selectively kills ALDH positive cells, a marker of cancer stem cells, causes spheroid 3D cultures collapse in vitro and impairs their growth in vivo. These results suggest that SCD1 may be a critical target in lung cancer tumor-initiating cells and further studies are needed to assess the role of this enzyme in lung cancer. An increasing number of literature points to the Hippo (and their effectors YAP/ TAZ) and to the Wnt/β-catenin signaling pathways as key factors in the development of cancer. Notably, SCD1 has been shown to be involved in the secretion and maturation of active wnt ligands, contributing to the activation of the β-catenin signaling. We report here, using primary cell cultures from adenocarcinoma of the lung, that YAP and TAZ are required for the generation of 3D cultures, as silencing of both genes completely abrogated the capability of generating lung cancer spheroids. Moreover, simultaneously silencing of YAP and TAZ reduced the mRNA levels of OCT4, Nanog and ALDH. We demonstrated that both silencing of SCD1 and its pharmacological inhibition determined a decrease in the expression and nuclear localization of both YAP and TAZ. Moreover, when SCD1 was inhibited, YAP and TAZ transcriptional activity was reduced. We also demonstrated that SCD1 blockade induced a dramatic reduction of the Axin2 mRNA level, one of the β-catenin target genes and a decreased in the β-catenin transcriptional activity, without affecting β-catenin protein expression. YAP and TAZ downregulation induced by SCD1 blockade could be rescued by the addition of exogenous wnt3a ligand, thus indicating that the active β-catenin signaling is necessary for YAP and TAZ stabilization. Ultimately, we observed that the ubiquitin ligase β-TrcP is involved in the SCD1 mediated degradation of YAP and TAZ. These data, overall, demonstrate for the first time the involvement of SCD1 in the regulation of the Hippo pathway and β-catenin pathway in lung cancer 3D spheroid cultures, pointing to lipid metabolism as regulator of cancer stem features. Moreover, these results can be the starting point for further studies focused on the regulation of SCD1 in cancer stem cells, suggesting a new perspective for improving chemotherapeutic responses in cancer treatment, centered on SCD1 inhibition. Citation Format: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Giovanni Sorrentino, Giannino Del Sal, Alfredo Budillon, Gennaro Ciliberto, Rita Mancini. Stearoyl-CoA-Desaturase (SCD1) regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1052.