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Common chromosomal fragile site FRA16D tumor suppressor WWOX gene expression and metabolic reprograming in cells
Sonia Dayan1, Louise V O'Keefe, Amanda Choo
1Discipline of Genetics, School of Molecular and Biomedical Sciences and ARC Special Research Centre for the Molecular Genetics of Development, The University of Adelaide, Adelaide, SA, 5005, Australia.
Abstract:
The WWOX gene spans the FRA16D common chromosomal fragile site and is able to suppress tumor growth. FRA16D is a frequent site of DNA instability in cancer resulting in reduced levels of WWOX expression. Altered levels of WWOX have been shown to affect metabolism. Whereas metabolic reprograming of cells from oxidative phosphorylation to aerobic glycolysis is a major hallmark of tumors, the relationship between common chromosomal fragile site genes and altered metabolism has been unclear. Here we report that altering metabolism from glycolysis to oxidative phosphorylation causes stable increase in steady-state levels of transcripts of the WWOX gene. Consistent with this, exposure to hypoxic conditions, in which cells rely on glycolysis, causes a downregulation of WWOX mRNA. The function of WWOX is therefore intimately integrated with metabolism, as WWOX not only contributes to the metabolic state of cells, its transcript levels are also linked to intracellular metabolic state.
Insights
The WWOX gene, linked to tumor suppression, shows altered expression based on cellular metabolism. Shifting cells to oxidative phosphorylation increases WWOX gene transcripts, while glycolysis downregulates them.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- The WWOX gene, located at the FRA16D fragile site, is known for tumor suppression.
- DNA instability at FRA16D in cancer leads to decreased WWOX expression.
- Altered WWOX levels impact cellular metabolism, but its link to metabolic reprogramming in cancer is unclear.
Purpose of the Study:
- To investigate the relationship between cellular metabolism and WWOX gene expression.
- To understand how metabolic shifts influence WWOX transcript levels.
Main Methods:
- Manipulating cellular metabolism between glycolysis and oxidative phosphorylation.
- Analyzing WWOX gene transcript levels under varying metabolic conditions.
- Exposing cells to hypoxic conditions to induce glycolysis.
Main Results:
- Switching cellular metabolism from glycolysis to oxidative phosphorylation resulted in a stable increase in WWOX gene transcript levels.
- Hypoxic conditions, which promote glycolysis, led to a downregulation of WWOX mRNA.
- WWOX expression is sensitive to the intracellular metabolic state.
Conclusions:
- WWOX gene expression is intricately linked to cellular metabolism.
- Metabolic state directly influences WWOX transcript levels, highlighting a feedback loop.
- This finding deepens the understanding of fragile site gene function in cancer metabolism.
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