title: Hyperglycemia triggers HIPK2 protein degradation.
abstract: Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2. We focused on the effect of high glucose (HG) on HIPK2 protein stability and the underlying mechanisms. We found that HG reduced HIPK2 protein levels, therefore impairing HIPK2-induced p53 apoptotic activity. HG-triggered HIPK2 protein downregulation was rescued by both proteasome inhibitor MG132 and by protein phosphatase inhibitors Calyculin A (CL-A) and Okadaic Acid (OA). Looking for the phosphatase involved, we found that protein phosphatase 2A (PP2A) induced HIPK2 degradation, as evidenced by directly activating PP2A with FTY720 or by silencing PP2A with siRNA in HG condition. The effect of PP2A on HIPK2 protein degradation could be in part due to hypoxia-inducible factor-1 (HIF-1) activity which has been previously shown to induce HIPK2 proteasomal degradation through several ubiquitin ligases. Validation analysed performed with HIF-1α dominant negative or with silencing of Siah2 ubiquitin ligase clearly showed rescue of HG-induced HIPK2 degradation. These findings demonstrate how hyperglycemia, through a complex protein cascade, induced HIPK2 downregulation and consequently impaired p53 apoptotic activity, revealing a novel link between diabetes/obesity and tumor resistance to therapies.
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Baldari
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy.|Department of Medical Sciences, Tumor Biology Unit, University 'G. d'Annunzio', 66013 Chieti, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Garufi
authors.affiliation: Department of Experimental Medicine, Pasteur-Fondazione Cenci Bolognetti Institute, Sapienza University, 00100 Rome, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Granato
authors.affiliation: U.O.C. Clinical Pathology, A.C.O., San Filippo Neri Hospital, 00100 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cuomo
authors.affiliation: Department of Systems Medicine, University Tor Vergata, 00133 Rome, Italy.
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Pistritto
authors.affiliation: Department of Experimental Medicine, Pasteur-Fondazione Cenci Bolognetti Institute, Sapienza University, 00100 Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy.|Department of Medical Sciences, Tumor Biology Unit, University 'G. d'Annunzio', 66013 Chieti, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
mesh_terms: D017209:Apoptosis; D001786:Blood Glucose; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2
keywords: HIPK2; PP2A; cancer; hyperglycemia; p53