PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma.
Journal
Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004
Informations de publication
Date de publication:
17 Sep 2022
17 Sep 2022
Historique:
received:
18
02
2022
accepted:
31
08
2022
revised:
25
08
2022
entrez:
17
9
2022
pubmed:
18
9
2022
medline:
18
9
2022
Statut:
epublish
Résumé
Glioblastoma is a highly aggressive brain tumor for which there is no cure. The metabolic enzyme 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is essential for glioblastoma stem-like cell (GSC) survival but its mode of action is unclear. Understanding the role of PFKFB4 in tumor cell survival could allow it to be leveraged in a cancer therapy. Here, we show the importance of PFKFB4 for glioblastoma growth in vivo in an orthotopic patient derived mouse model. In an evaluation of patient tumor samples of different cancer entities, PFKFB4 protein was found to be overexpressed in prostate, lung, colon, mammary and squamous cell carcinoma, with expression level correlating with tumor grade. Gene expression profiling in PFKFB4-silenced GSCs revealed a downregulation of hypoxia related genes and Western blot analysis confirmed a dramatic reduction of HIF (hypoxia inducible factor) protein levels. Through mass spectrometric analysis of immunoprecipitated PFKFB4, we identified the ubiquitin E3 ligase, F-box only protein 28 (FBXO28), as a new interaction partner of PFKFB4. We show that PFKFB4 regulates the ubiquitylation and subsequent proteasomal degradation of HIF-1α, which is mediated by the ubiquitin ligase activity of FBXO28. This newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF-1α in cancer cells.
Identifiants
pubmed: 36115843
doi: 10.1038/s41389-022-00433-3
pii: 10.1038/s41389-022-00433-3
pmc: PMC9482633
doi:
Types de publication
Journal Article
Langues
eng
Pagination
57Informations de copyright
© 2022. The Author(s).
Références
Nucleic Acids Res. 2016 Dec 15;44(22):11033
pubmed: 27683222
Curr Oncol Rep. 2019 Jan 22;21(1):6
pubmed: 30671662
Front Oncol. 2018 Jul 02;8:249
pubmed: 30013951
Cancer Res. 2003 Sep 15;63(18):5821-8
pubmed: 14522905
Acta Neuropathol. 2007 Aug;114(2):97-109
pubmed: 17618441
BMC Cancer. 2008 Nov 16;8:335
pubmed: 19014607
Cancer Res. 2009 Dec 1;69(23):9065-72
pubmed: 19920198
Genes Dev. 1998 Jan 15;12(2):149-62
pubmed: 9436976
Cancer Res. 1998 Dec 1;58(23):5280-4
pubmed: 9850048
Clin Cancer Res. 2009 Nov 1;15(21):6541-50
pubmed: 19861460
Oncogene. 2012 Jul 5;31(27):3235-43
pubmed: 22056879
Cancer Res. 2004 Oct 1;64(19):7011-21
pubmed: 15466194
Biochem Biophys Res Commun. 2016 Jul 29;476(3):146-52
pubmed: 27181362
Nature. 2006 Dec 7;444(7120):756-60
pubmed: 17051156
EMBO Mol Med. 2013 Jul;5(7):1067-86
pubmed: 23776131
Genes Dev. 2000 Jan 1;14(1):34-44
pubmed: 10640274
Cancer Res. 2000 Mar 15;60(6):1541-5
pubmed: 10749120
Cancer Cell. 2010 Jul 13;18(1):23-38
pubmed: 20609350
Cancer Discov. 2012 Apr;2(4):328-43
pubmed: 22576210
Biofactors. 1999;10(1):1-14
pubmed: 10475585
J Biol Chem. 2006 Jun 2;281(22):15215-26
pubmed: 16565084
EMBO J. 2000 Aug 15;19(16):4298-309
pubmed: 10944113
Oncotarget. 2014 Aug 30;5(16):6670-86
pubmed: 25115398
Mol Pharm. 2009 May-Jun;6(3):738-46
pubmed: 19296675
BMC Cancer. 2008 Nov 04;8:320
pubmed: 18983642
Trends Cancer. 2020 Mar;6(3):223-235
pubmed: 32101725
Nature. 2018 Apr;556(7700):249-254
pubmed: 29615789
Nature. 2004 Nov 18;432(7015):396-401
pubmed: 15549107
Mol Metab. 2019 Feb;20:1-13
pubmed: 30553771
Acta Pharm Sin B. 2015 Sep;5(5):378-89
pubmed: 26579469
Biochimie. 2005 Nov;87(11):1005-10
pubmed: 15925437
Cell. 2013 Oct 10;155(2):462-77
pubmed: 24120142
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14094-9
pubmed: 18780787
Int J Mol Sci. 2020 Dec 29;22(1):
pubmed: 33383924
Cancer Cell. 2014 Oct 13;26(4):455-64
pubmed: 25314076
J Neuropathol Exp Neurol. 2019 Sep 1;78(9):865-870
pubmed: 31369092
Cancer Invest. 2008 Jun;26(5):535-42
pubmed: 18568776
PLoS One. 2016 Feb 22;11(2):e0149492
pubmed: 26900704
Cell Death Differ. 2012 Feb;19(2):284-94
pubmed: 21818118
Urol Oncol. 2012 Nov-Dec;30(6):893-9
pubmed: 21396842
J Exp Clin Cancer Res. 2021 Sep 30;40(1):308
pubmed: 34593007
Clin Cancer Res. 2010 May 15;16(10):2715-28
pubmed: 20442299
Cancer Drug Resist. 2020;3(2):199-208
pubmed: 32566921
Sci Rep. 2020 Sep 16;10(1):15195
pubmed: 32938997
Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:379-403
pubmed: 30625281
Cancer Metab. 2013 Feb 04;1(1):8
pubmed: 24280138
Front Cell Dev Biol. 2017 Apr 26;5:43
pubmed: 28491867
Oncogene. 2010 Feb 4;29(5):625-34
pubmed: 19946328
Cell Cycle. 2017 Apr 18;16(8):737-745
pubmed: 27753527
J Cell Biochem. 2011 Dec;112(12):3882-90
pubmed: 21964756
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
Oncotarget. 2015 Jul 20;6(20):18001-11
pubmed: 26221874
J Clin Neurosci. 2008 Sep;15(9):1036-42
pubmed: 18621534
Free Radic Biol Med. 2017 Dec;113:311-322
pubmed: 29032224