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Review
. 2018 Sep 3;17(1):134.
doi: 10.1186/s12943-018-0882-1.

The Role of YAP/TAZ Activity in Cancer Metabolic Reprogramming

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Free PMC article
Review

The Role of YAP/TAZ Activity in Cancer Metabolic Reprogramming

Xiaodong Zhang et al. Mol Cancer. .
Free PMC article

Abstract

In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.

Keywords: Fatty acids; Gluconeogenesis; Glutamine; Glycolysis; Metabolic reprograming; Mevalonate; YAP/TAZ.

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The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
A simplified illustration of HIPPO signaling pathway. The Hippo signaling pathway is mainly comprised of MST1/2, Sav1, LATS1/2, Mob, YAP and/or its paralog TAZ. When the Hippo pathway is “ON”, MST1/2 phosphorylates and activates LATS1/2, which in turn phosphorylates YAP/TAZ and inhibits YAP/TAZ activity, leading to YAP/TAZ cytoplasmic retention and binding to 14–3-3 proteins or proteasomal degradation. When the Hippo signaling pathway is “OFF”, MSAT1/2 and LATS1/2 are inactivated, the transcriptional coactivators YAP/TAZ cannot be phosphorylated by LATS1/2 and freely translocate to nucleus and bind to TEAD transcription factors, promoting the expression of downstream target genes, such as CTGF and CYR61, which are involved in growth, proliferation, and survival
Fig. 2
Fig. 2
A simplified illustration of YAP/TAZ and glycolysis. (a). Glycolysis upregulates the activity of PFK1 (phosphofructokinase) to promote YAP/TAZ transcriptional cooperation with TEAD factors, and form a PFK1-TEAD1-YAP/TAZ complex in cells nucleus. (b). Glycolysis activates YAP through the HBP (hexosamine biosynthesis pathway). YAP is O-GlcNAcylated by OGT (O-linked b-N-acetylglucosamine transferase). O-GlcNAcylation of YAP promotes its nuclear translocation and transcriptional activity. (c). MG (Methylglyoxal), a side-product of glycolysis, promotes YAP transcriptional cooperation with TEAD factors by reducing the binding of HSP90 and LATS1 and inhibiting LATS1 activity. (d). YAP-TEAD binds with the GLUT3 promoter to directly regulate the transcription of GLUT3 and then promotes glycolysis in tumor cells. (e). FOXC2 (forkhead box protein C2) interacts with YAP and TEAD in cells nucleus to activate YAP, and then the activation of YAP upregulates the expression of HK2 to promote cells glycolysis. (f) YAP-TEAD directly binds with the two site (GGAATT/GGAATC) in the promoter region of lncRNA BCAR4 to upregulate the expression and transcriptional activity of HK2 and PFKFB3 to promote cells glycolysis
Fig. 3
Fig. 3
A simplified illustration of YAP/TAZ and fatty acids. (a). SCD1 promotes the synthesis of unsaturated fatty acids. Unsaturated fatty acids activate Wnt ligand. Activation of the Wnt ligand combined with FZD4 receptor to damage the destruction complex, ultimately stabilize β-catenin and YAP/TAZ protein activity and promote β-catenin and YAP/TAZ accumulation in the nucleus to play the function role of transcription regulation. (Destruction complex: APC, Axin1, GSK3, β-TrcP). (b). Free fatty acid induces high expression of JCAD, which in turn binds to the domain of LATS2 kinase and inhibits the ability of LATS2 to phosphorylate YAP, leading to activate YAP transcription by dephosphorylating and promote YAP nuclear translocation to promote hepatoma cell proliferation. (c). Palmitate promotes YAP transcriptional activity in a F-actin-dependent manner. (d). Palmitate attaches to TEAD cysteine residues to palmitoylate TEAD, stabilizes TEAD binding to YAP/TAZ and promotes their transcriptional activity
Fig. 4
Fig. 4
A simplified illustration of YAP/TAZ and mevalonate. HMG CoA produces mevalonate through the activity of the HMG CoA reductase (HMGCR). Geranylgeranyl pyrophosphate (GGPP), the intermediate of mevalonate metabolism, activates RHO to promote YAP/TAZ transcriptional cooperation with TEAD factors in cells nucleus. Then YAP/TAZ-TEAD binds the specific sites in the RHAMM promoter to play the function role of transcription regulation. The transcription of HMG CoA reductase (HMGCR) also can be inhibited by Statins or activated by SREBP transcription factors, which can be upregualted by mutant p53. This explains why some small-molecule inhibitors such as statins could inhibit the nuclear localization and transcriptional activity of YAP/TAZ
Fig. 5
Fig. 5
A simplified illustration of YAP/TAZ and glutaminolysis. (a). Activation of YAP/TAZ upregulates the expression of glutamine by promoting the expression and transcriptional activity of glutamine synthetase (GLUL). (b). YAP/TAZ upregulates the expression of glutaminase (GLS1) to promote glutaminolysis

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