Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation

Bulusu, V. et al. (2017) Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Reports, 18(3), pp. 647-658. (doi:10.1016/j.celrep.2016.12.055) (PMID:28099844) (PMCID:5276806)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Bulusu, Dr Vinay and Schug, Dr Zachary and Blyth, Dr Karen and Gottlieb, Professor Eyal and Van Den Broek, Mr Niels and Vazquez, Alexei and Tumanov, Dr Sergey and Mackay, Dr Gillian and Kamphorst, Dr Jurre
Authors: Bulusu, V., Tumanov, S., Michalopoulou, E., Van Den Broek, N., Mackay, G., Nixon, C., Dhayade, S., Schug, Z. T., Vande Voorde, J., Blyth, K., Gottlieb, E., Vazquez, A., and Kamphorst, J. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Cell Reports 18(3):647-658
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
655161The effect of tumour microenvironment on the metabolism of pancreatic cancer cellsJurre KamphorstCancer Research UK (CAN-RES-UK)17728ICS - BEATSON INSTITUTE FOR CANCER RES.
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)18076RI CANCER SCIENCES