Orateur
Description
The rewiring of glucose metabolism from mitochondrial respiration to
fermentation is a hallmark of cancer. This metabolic adaptation has been exploited in
ongoing therapeutic and diagnostic strategies. Notably, treating cancer cells with the
glucose analog 2-deoxy-D-glucose (2DG) reduces their proliferation presumably by
dampening the rate of glycolysis. However, this treatment leads to frequent resistance,
through mechanisms that remain incompletely characterized. This issue is important
to improve the efficacy of this compound while preventing resistance, and to rationalize
its use in the clinics, either alone or in combinatorial approaches.
We are using fission yeast as a new model to understand the cellular effects of
2DG and how cells evade its toxicity. Indeed, we accumulated evidence that new
resistance mechanisms exist in this species, which were not identified in studies
previously performed in budding yeast and other model systems. Two epigenetic
regulators, SAGA and SWI/SNF, appear to have critical roles in 2DG resistance in
fission yeast, suggesting a new chromatin-based mechanism. In particular, our
preliminary data suggest a differential degree of action within the SAGA complex,
revealing a leading role for the histone acetyl transferase subunit in 2DG resistance
whose molecular mechanisms have yet to be determined.
