PXD009807

PXD009807 is an original dataset announced via ProteomeXchange.

Title	Glycolysis enzyme PFKFB4 enhances HIF1a transcriptional activity by blocking the ubiquitin E3 ligase FBXO28 in glioblastoma
Description	Glioblastoma is one of the most aggressive primary brain tumours in adults, with a dismal median overall survival of only 14 months after diagnosis1,2. Glioblastoma stem-like cells (GSCs), are particularly resistant to current therapies3,4, capable of self-renewal and tumour initiation5,6 and are hence thought to be major contributors to patient relapse. Glycolysis gene 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is an essential gene for GSC survival, and is upregulated in these cells compared with in normal brain7. However, the mode of action of PFKFB4 in GSCs is unknown. Here we show a new role for PFKFB4 in the regulation of Hypoxia Inducible Factor 1 alpha (HIF1α) in GSCs. In a metabolic tracing study, we found that silencing PFKFB4 in GSCs resulted in a global downregulation of glucose metabolism. Gene expression profiling of PFKFB4-silenced GSCs revealed a downregulation of HIF1α target genes, and HIF1α protein levels are dramatically reduced in PFKFB4-silenced GSCs and other cancer cell lines. Finally, 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, which we show to regulate ubiquitylation and subsequent proteasomal degradation of HIF1α. Crucially, this newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF1α in a cancer specific manner. Compounds which disrupt the interaction between PFKFB4 and FBXO28 could be interesting therapeutic agents against glioblastoma and other cancer entities in which PFKFB4 regulates HIF1α stability.
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_10:13:47.104.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD009807
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Uwe Warnken
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2018-05-17 02:11:00	ID requested
⏵ 1	2024-10-07 10:13:52	announced

Phillips E, Balss J, Bethke F, Pusch S, Christen S, Hielscher T, Schn, ö, lzer M, Fletcher MNC, Habel A, Tessmer C, Brenner LM, G, ö, ttmann M, Capper D, Herold-Mende C, von Deimling A, Fendt SM, Goidts V, signaling in glioblastoma. Oncogenesis, 11(1):57(2022) [pubmed]

10.1038/s41389-022-00433-3;

10.6019/PXD009807;

curator keyword: Biomedical

submitter keyword: LC-MSMS,Human. glioblastoma

Martina Schnölzer
contact affiliation	Functional Proteome Analysis, German Cancer Research Center(DKFZ)
contact email	m.schnoelzer@dkfz.de
lab head
Uwe Warnken
contact affiliation	German Cancer Research Center Heidelberg, Clinical Cooperation Unit Neurooncology B320
contact email	u.warnken@dkfz.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD009807
     1. Label: PRIDE project
     2. Name: Glycolysis enzyme PFKFB4 enhances HIF1a transcriptional activity by blocking the ubiquitin E3 ligase FBXO28 in glioblastoma