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      Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress


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          Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.


          We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O 2) and hypoxic (1% O 2) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.


          In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.


          Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-018-0892-2) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

          The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Hypoxia signalling in cancer and approaches to enforce tumour regression.

            Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.
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              Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer.

              Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a profound impact on clinical outcomes in cancer patients. At decreased oxygen tensions, hypoxia-inducible factors (HIFs) 1 and 2 are stabilized and mediate a hypoxic response, primarily by acting as transcription factors. HIFs exert differential effects on tumor growth and affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, vascularization/angiogenesis, genetic instability, tumor metabolism, tumor immune responses, and invasion and metastasis. As a consequence, HIFs mediate resistance to chemo- and radiotherapy and are associated with poor prognosis in cancer patients. Intriguingly, perivascular tumor cells can also express HIF-2α, thereby forming a "pseudohypoxic" phenotype that further contributes to tumor aggressiveness. Therefore, therapeutic targeting of HIFs in cancer has the potential to improve treatment efficacy. Different strategies to target hypoxic cancer cells and/or HIFs include hypoxia-activated prodrugs and inhibition of HIF dimerization, mRNA or protein expression, DNA binding capacity, and transcriptional activity. Here we review the functions of HIFs in the progression and treatment of malignant solid tumors. We also highlight how HIFs may be targeted to improve the management of patients with therapy-resistant and metastatic cancer.

                Author and article information

                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                4 September 2018
                4 September 2018
                : 37
                : 216
                [1 ]GRID grid.412644.1, Department of General Surgery, , The Fourth Affiliated Hospital of China Medical University, ; 4 Chongshan East Street, Shenyang, Liaoning 110032 People’s Republic of China
                [2 ]Department of Oncology, Tumour Angiogenesis and Microenvironment Laboratory (TAML), The First Affiliated Hospital of Jinzhou Medical College, Jinzhou, China
                [3 ]ISNI 0000 0004 1806 3501, GRID grid.412467.2, Department of Pathology, , The Shengjing Hospital of China Medical University, ; Shenyang, Liaoning China
                [4 ]ISNI 0000 0000 9678 1884, GRID grid.412449.e, Department of Biochemistry and Molecular Biology, College of Basic Medicine, , China Medical University, ; Shenyang, China
                [5 ]ISNI 0000 0000 9678 1884, GRID grid.412449.e, Department of Immunology, College of Basic Medicine, , China Medical University, ; Shenyang, China
                [6 ]ISNI 0000 0004 1798 5889, GRID grid.459742.9, Department of Hepatobiliary Surgery, , Liaoning Cancer Hospital and Institute, ; Shenyang, China
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                : 25 April 2018
                : 24 August 2018
                Funded by: Natural Scientific Foundation of China
                Award ID: 81472302
                Award Recipient :
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                yes-associated protein (yap),hypoxia,hif-1α,hcc,glycolysis
                Oncology & Radiotherapy
                yes-associated protein (yap), hypoxia, hif-1α, hcc, glycolysis


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