Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

M. Abu-Remaileh, R. I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

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 1α (HIF1α) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1α and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1α 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.

Original languageAmerican English
Pages (from-to)1805-1814
Number of pages10
JournalCell Death and Differentiation
Volume21
Issue number11
DOIs
StatePublished - 1 Nov 2014

Bibliographical note

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

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