Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation

Publication date: 17 January 2017
Source:Cell Reports, Volume 18, Issue 3
Author(s): Vinay Bulusu, Sergey Tumanov, Evdokia Michalopoulou, Niels J. van den Broek, Gillian MacKay, Colin Nixon, Sandeep Dhayade, Zachary T. Schug, Johan Vande Voorde, Karen Blyth, Eyal Gottlieb, Alexei Vazquez, Jurre J. Kamphorst
Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation.

Graphical abstract

Teaser

Acetyl-CoA synthetase 2 (ACSS2) generates acetyl-CoA from acetate and is important for tumor growth. Bulusu et al. show that, in hypoxic tumor regions, ACSS2 is prominently expressed in the nuclei of tumor cells. Here it maintains histone acetylation by recapturing acetate released by histone deacetylases so it can be re-used for acetylation.


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