Survival of cancer cells in the harsh tumor microenvironment, characterized by oxygen and glucose deprivation, requires rapid initiation of cytoprotective measures. Metabolites whose levels change during stress are ideal signaling cues, particularly if used in post-translational modifications of stress-responsive signal transducers. In cancer cells during oxygen or glucose deprivation, cellular acetate increases to provide substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2). Acetyl CoA production by nuclear, rather than cytosolic, Acss2 promotes acetylation and complex formation of the stress-responsive transcription factor Hypoxia Inducible Factor 2 (HIF-2) with the acetyltransferase/coactivator Creb binding protein (Cbp). In addition to promoting de novo transcription, Acss2 and HIF-2 act in concert to regulate global histone epigenetic marks induced by Cbp. Finally, exogenous acetate augments Acss2/HIF-2 dependent growth and metastasis of cancer cells in culture and in mice. Thus, the acetate switch links nutrient intake and stress signaling with cancer growth and metastasis in mammals.
