| First Author | Abu-Remaileh M | Year | 2014 |
| Journal | Cell Death Differ | Volume | 21 |
| Issue | 11 | Pages | 1805-14 |
| PubMed ID | 25012504 | Mgi Jnum | J:230137 |
| Mgi Id | MGI:5755555 | Doi | 10.1038/cdd.2014.95 |
| Citation | Abu-Remaileh M, et al. (2014) Tumor suppressor WWOX regulates glucose metabolism via HIF1alpha modulation. Cell Death Differ 21(11):1805-14 |
| abstractText | The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1alpha (HIF1alpha) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1alpha and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1alpha levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism. |
