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PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Author

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  • Valeria Iansante

    (Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research)

  • Pui Man Choy

    (Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research)

  • Sze Wai Fung

    (Section of Inflammation and Signal Transduction, Imperial College)

  • Ying Liu

    (The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
    Henan Cancer Hospital)

  • Jian-Guo Chai

    (Section of Molecular Immunology, Imperial College)

  • Julian Dyson

    (Section of Molecular Immunology, Imperial College)

  • Alberto Del Rio

    (Institute of Organic Synthesis and Photoreactivity, National Research Council)

  • Clive D’Santos

    (Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre)

  • Roger Williams

    (Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research
    Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research)

  • Shilpa Chokshi

    (Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research)

  • Robert A Anders

    (The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine)

  • Concetta Bubici

    (Section of Inflammation and Signal Transduction, Imperial College
    Present address: Department of Life Sciences, Division of Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK.)

  • Salvatore Papa

    (Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research)

Abstract

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism.

Suggested Citation

  • Valeria Iansante & Pui Man Choy & Sze Wai Fung & Ying Liu & Jian-Guo Chai & Julian Dyson & Alberto Del Rio & Clive D’Santos & Roger Williams & Shilpa Chokshi & Robert A Anders & Concetta Bubici & Salv, 2015. "PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8882
    DOI: 10.1038/ncomms8882
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    Cited by:

    1. Ashna Dhoonmoon & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Chun Wai Wong & Christos Evangelou & Kieran N. Sefton & Rotem Leshem & Wei Zhang & Vishaka Gopalan & Sorayut Chattrakarn & Macarena Lucia Fernandez Carro & Erez Uzuner & Holly Mole & Daniel J. Wilcock, 2023. "PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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