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Review
. 2020 Jan 25:316:108917.
doi: 10.1016/j.cbi.2019.108917. Epub 2019 Dec 12.

Stearoyl-CoA desaturase and tumorigenesis

Kohtaro Kikuchi  1 , Hidekazu Tsukamoto  2
Affiliations
Review

Stearoyl-CoA desaturase and tumorigenesis

Kohtaro Kikuchi et al. Chem Biol Interact. .

Abstract

Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also stimulates canonical Wnt pathway and YAP activation in support of stemness and tumorigenesis. SCD facilitates metabolic reprogramming in cancer which is mediated, at least in part, by regulation of AKT, AMPK, and NF-kB via MUFAs. Our research has revealed the novel positive loop to amplify Wnt signaling through stabilization of LRP5/6 in both hepatic stellate cells and liver tumor-initiating stem cell-like cells. As such, this loop is pivotal in promoting liver fibrosis and liver tumor development. This review summarizes the mechanisms of SCD-mediated tumor promotion described by recent studies and discusses the future prospect for SCD-mediated signaling crosstalk as a potential therapeutic target for cancer.

Keywords: Hepatic stellate cells; Wnt; YAP; β-catenin.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1:
Figure 1:
This figure depicts how SCD establishes tumor-promoting pathways. SCD produces MUFAs such as palmitoleate (16:1) which is used to lipidate Wnt proteins via Porcupine acyltransferase for their extracellular release. Scd1/2 is a Wnt-target gene and its transcription is amplified by association of β-catenin with SREBP-1 and NF-Y bound to the respective elements in the Scd1/2 proximal promoter. MUFAs produced by SCD inhibit HuR nuclear translocation via impairment of TNPO1-Ran1 association. Increased HuR in cytosol stabilizes Lrp5/6 mRNA via its binging to their AU-rich elements. LRP 5/6 are functional co-receptors of Wnt pathway and their expression, optimal Wnt pathway, and β-catenin/TCF-dependent gene transcription are dependent on SCD activity. Wnt-YAP positive crosstalk may be mediated by Wnt binding to Fz and ROR 1/2, the G-protein-coupled receptor, activating the catalytic Gα12/13 subunit, which inhibits LATS 1/2 via activation of Rho GTPase, causing stabilization and nuclear translocation of YAP/TAZ. Rho is also activated by geranylgeranyl diphosphate (GGPP), lipid metabolites in lanosterol-cholesterol synthetic pathway via prenylation of Rho. Wnt-YAP positive crosstalk is also mediated by TRIB2, a Wnt target gene which activates YAP by binding βTrCP and interfering YAP degradation. Wnt-YAP reciprocal regulation may also take place. Dvl is the key adaptor protein for Wnt pathway, phosphorylation of Dvl attracts the β-catenin destruction complex and causes inhibitory phosphorylation of GSK3β for stabilization of β-catenin. Dvl with the nuclear export signal, causes p-YAP cytosolic translocation and localization, which are stimulated by the tumor suppressor p53-LATS2 and LKB1-AMPK axes. Thus, SCD, which establishes and amplifies Wnt pathway activation loop, likely establishes crosstalk with these interactive pathways with YAP to promote tumor development and these crosstalk interfaces may serve as potential therapeutic targets.
See this image and copyright information in PMC

References

    1. AM AL, Syed DN, and Ntambi JM, Insights into Stearoyl-CoA Desaturase-1 Regulation of Systemic Metabolism. Trends Endocrinol Metab, 2017. 28(12): p. 831–842. 10.1016/j.tem.2017.10.003. 29089222. - DOI - PMC - PubMed
    1. Miyazaki M, Kim YC, and Ntambi JM, A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis. J Lipid Res, 2001. 42(7): p. 1018–24. 11441127. - PubMed
    1. Miyazaki M, et al., Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. J Biol Chem, 2004. 279(24): p. 25164–71. 10.1074/jbc.M402781200. 15066988. - DOI - PubMed
    1. Mitro N, et al., The nuclear receptor LXR is a glucose sensor. Nature, 2007. 445(7124): p. 219–23. 10.1038/nature05449. 17187055. - DOI - PubMed
    1. Iizuka K, et al., Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A, 2004. 101(19): p. 7281–6. 10.1073/pnas.0401516101. 15118080. - DOI - PMC - PubMed

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