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

Cell Reports

Niels J. van den Broek¹  Eyal Gottlieb¹  Sandeep Dhayade¹  Karen Blyth¹  Sergey Tumanov¹  Gillian MacKay¹  Colin Nixon¹  Evdokia Michalopoulou¹  Zachary T. Schug¹  Alexei Vazquez¹  Jurre J. Kamphorst¹  Vinay Bulusu¹  Johan Vande Voorde¹ 

[1] Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK;

关键词: acetate;    acetyl-CoA synthetase 2;    cancer metabolism;    enzyme localization;    histone acetylation;    histone deacetylation;    hypoxia;    lipogenesis;    metabolite compartmentalization;    stable isotope tracing;   

DOI  :  10.1016/j.celrep.2016.12.055

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown