PMID- 27901482
OWN - NLM
STAT- MEDLINE
DCOM- 20180305
LR  - 20211204
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Jan 3
TI  - Hyperglycemia triggers HIPK2 protein degradation.
PG  - 1190-1203
LID - 10.18632/oncotarget.13595 [doi]
AB  - 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-1alpha 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.
FAU - Baldari, Silvia
AU  - Baldari S
AD  - Department of Research, Advanced Diagnostics, and Technological Innovation, 
      Regina Elena National Cancer Institute, 00144 Rome, Italy.
FAU - Garufi, Alessia
AU  - Garufi A
AD  - Department of Research, Advanced Diagnostics, and Technological Innovation, 
      Regina Elena National Cancer Institute, 00144 Rome, Italy.
AD  - Department of Medical Sciences, Tumor Biology Unit, University 'G. d'Annunzio', 
      66013 Chieti, Italy.
FAU - Granato, Marisa
AU  - Granato M
AD  - Department of Experimental Medicine, Pasteur-Fondazione Cenci Bolognetti 
      Institute, Sapienza University, 00100 Rome, Italy.
FAU - Cuomo, Laura
AU  - Cuomo L
AD  - U.O.C. Clinical Pathology, A.C.O., San Filippo Neri Hospital, 00100 Rome, Italy.
FAU - Pistritto, Giuseppa
AU  - Pistritto G
AD  - Department of Systems Medicine, University Tor Vergata, 00133 Rome, Italy.
FAU - Cirone, Mara
AU  - Cirone M
AD  - Department of Experimental Medicine, Pasteur-Fondazione Cenci Bolognetti 
      Institute, Sapienza University, 00100 Rome, Italy.
FAU - D'Orazi, Gabriella
AU  - D'Orazi G
AD  - Department of Research, Advanced Diagnostics, and Technological Innovation, 
      Regina Elena National Cancer Institute, 00144 Rome, Italy.
AD  - Department of Medical Sciences, Tumor Biology Unit, University 'G. d'Annunzio', 
      66013 Chieti, Italy.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Blood Glucose)
RN  - 0 (Carrier Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.7.1.- (HIPK2 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - Apoptosis
MH  - Blood Glucose
MH  - Carrier Proteins/*metabolism
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hyperglycemia/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - Models, Biological
MH  - Protein Phosphatase 2/metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proteolysis
MH  - Tumor Suppressor Protein p53/metabolism
PMC - PMC5352047
OTO - NOTNLM
OT  - HIPK2
OT  - PP2A
OT  - cancer
OT  - hyperglycemia
OT  - p53
COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest.
EDAT- 2016/12/03 06:00
MHDA- 2018/03/06 06:00
PMCR- 2017/01/03
CRDT- 2016/12/01 06:00
PHST- 2016/08/04 00:00 [received]
PHST- 2016/11/08 00:00 [accepted]
PHST- 2016/12/03 06:00 [pubmed]
PHST- 2018/03/06 06:00 [medline]
PHST- 2016/12/01 06:00 [entrez]
PHST- 2017/01/03 00:00 [pmc-release]
AID - 13595 [pii]
AID - 10.18632/oncotarget.13595 [doi]
PST - ppublish
SO  - Oncotarget. 2017 Jan 3;8(1):1190-1203. doi: 10.18632/oncotarget.13595.