TY - JOUR
T1 - Coordinate regulation of stress signaling and epigenetic events by Acss2 and HIF-2 in cancer cells
AU - Chen, Rui
AU - Xu, Min
AU - Nagati, Jason
AU - Garcia, Joseph A.
N1 - Funding Information:
These studies were supported by funds provided by the Department of Veterans Affairs (VA Merit Grant I01BX000446 to J.G.) and the National Institutes of Health (R01 Grant HL108104 and HL130142 to J.G.). We thank Ko Uyeda for insightful comments regarding acetyl CoA metabolism, Ralph J. Deberardinis and Andrew Mullen for assistance with acetate-dependent lipid determinations, Sanhua Fang and Chun-Li Zhang for assistance with immunofluorescence assays, Bob Gerard and Rolf Brekken for guidance with the in vitro tumor assays, and Alok Das and Richard Hogg for expert technical assistance.
Publisher Copyright:
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2017/12
Y1 - 2017/12
N2 - 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 exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2α (HIF-2α) subunit by the acetyltransferase/ coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2α complex formation. In addition to promoting de novo transcription, Cbp and HIF-2α act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis.
AB - 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 exposed to oxygen or glucose deprivation, there is an increase in cellular levels of acetate, a substrate for acetate-dependent acetyl CoA synthetase 2 (Acss2) that also stimulates translocation of Acss2 from the cytosol to the nucleus. Nuclear, but not cytosolic, Acss2 promotes acetylation of the stress-responsive Hypoxia Inducible Factor 2α (HIF-2α) subunit by the acetyltransferase/ coactivator Creb binding protein (Cbp), a process that facilitates stable Cbp/HIF-2α complex formation. In addition to promoting de novo transcription, Cbp and HIF-2α act in concert to regulate local histone 3 epigenetic marks. Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models. Thus, an acetate switch in mammals links nutrient intake and stress signaling with tumor growth and metastasis.
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U2 - 10.1371/journal.pone.0190241
DO - 10.1371/journal.pone.0190241
M3 - Article
C2 - 29281714
AN - SCOPUS:85039549122
SN - 1932-6203
VL - 12
JO - PLoS One
JF - PLoS One
IS - 12
M1 - e0190241
ER -