title: PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation.
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.
authors.affiliation: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
authors.forename: Valeria
authors.initials: V
authors.lastname: Iansante
authors.affiliation: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
authors.forename: Pui Man
authors.initials: PM
authors.lastname: Choy
authors.affiliation: Department of Medicine, Section of Inflammation and Signal Transduction, Imperial College, London W12 0NN, UK.
authors.forename: Sze Wai
authors.initials: SW
authors.lastname: Fung
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Division of Gastrointestinal and Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.|Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, Henan 450000, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Section of Molecular Immunology, Imperial College, London W12 0NN, UK.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
authors.affiliation: Department of Medicine, Section of Molecular Immunology, Imperial College, London W12 0NN, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.affiliation: Institute of Organic Synthesis and Photoreactivity, National Research Council, Bologna 40129, Italy.
authors.forename: Alberto
authors.identifier: http://orcid.org/0000-0002-1890-6797
authors.initials: A
authors.lastname: Del Rio
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: D'Santos
authors.affiliation: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.|Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.affiliation: Viral Hepatitis Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chokshi
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Division of Gastrointestinal and Liver Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Medicine, Section of Inflammation and Signal Transduction, Imperial College, London W12 0NN, UK.
authors.forename: Concetta
authors.initials: C
authors.lastname: Bubici
authors.affiliation: Cell Signaling and Cancer Laboratory, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Papa
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D015854:Up-Regulation; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D048055:Mitogen-Activated Protein Kinase 8; D011065:Poly(ADP-ribose) Polymerases; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C584083:PARP14 protein, human