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Review
. 2015 Mar;240(3):345-50.
doi: 10.1177/1535370214561956. Epub 2014 Dec 8.

The tumor suppressor WW domain-containing oxidoreductase modulates cell metabolism

Muhannad Abu-Remaileh  1 , Rami I Aqeilan  2
Affiliations
Review

The tumor suppressor WW domain-containing oxidoreductase modulates cell metabolism

Muhannad Abu-Remaileh et al. Exp Biol Med (Maywood). 2015 Mar.

Abstract

The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently altered in cancer. WWOX binds several proteins and thus is postulated to be involved in a variety of cellular processes. Interestingly, Wwox-knockout mice develop normally in utero but succumb to hypoglycemia and other metabolic defects early in life resulting in their death by 3-4 weeks of age. Cumulative evidence has linked WWOX with cellular metabolism including steroid metabolism, high-density lipoprotein cholesterol (HDL-C) metabolism, bone metabolism and, more recently, glucose metabolism. In this review, we discuss these evolving functions for WWOX and how its deletion affects cellular metabolism and neoplastic progression.

Keywords: WW domain-containing oxidoreductase; aerobic glycolysis; hypoxia-inducible transcription factor 1; metabolism; tumor suppressor.

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Figures

Figure 1
Figure 1
WWOX modulates cellular metabolism. Using animal models and cell culture it was demonstrated that WWOX alteration is associated with impaired steroidogenesis, low HDL-C levels, osteopenia and impaired osteoblast differentiation, hypoglycemia, and impaired ROS levels. (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
Model: WWOX modulates HIF1α activity through multiple pathways. Under hypoxic conditions, HIF1α is stabilized and binds HIF1β to transactivate many target genes resulting in increase rate of glycolysis and glucose uptake and inhibiting TCA cycle. Under these conditions, HIF1α is less hydroxylated by PHD2 and thus is not targeted for degradation mediated by Von Hippel–Lindau (VHL) E3 ligase complex. Our recent studies demonstrate that loss of tumor suppressor WWOX enhances HIF1α accumulation and its transcriptional function. WWOX physically interacts with HIF1α and induces its hydroxylation by PHD2 and so leads it to proteasomal degradation. WWOX also, inhibits HIF1α transactivation function. (A color version of this figure is available in the online journal.)
See this image and copyright information in PMC

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