Glioblastoma - one of the most Aggressive Primary Brain Tumors
Glioblastoma is a very aggressive brain tumor for which there is no cure. The metabolic enzyme 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is crucial for glioblastoma stem-like cell (GSC) survival but its mode of action is unclear.
Why it is important to Understand the Role of PFKFB4 in Tumor Cells
Understanding the role of PFKFB4 in tumor cell survival could allow it to be leveraged in 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 downregulation of hypoxia-related genes and Western blot analysis confirmed a dramatic reduction of HIF (hypoxia-inducible factor) protein levels.
A new Interaction Partner of PFKFB4 discovered through Mass Spectrometric Analysis
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.
Read more?
Phillips, E., Balss, J., Bethke, F. et al. PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma. Oncogenesis 11, 57 (2022).
https://doi.org/10.1038/s41389-022-00433-3
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#cancerresearch #glioblastoma #researchpaper #DKFZ #StemCells #massspectrometry
