PMID- 25689462
OWN - NLM
STAT- MEDLINE
DCOM- 20151223
LR  - 20181202
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 2
DP  - 2015
TI  - The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell 
      microenvironment.
PG  - e0116515
LID - 10.1371/journal.pone.0116515 [doi]
LID - e0116515
AB  - Optimal stress signaling by Hypoxia Inducible Factor 2 (HIF-2) during low oxygen 
      states or hypoxia requires coupled actions of a specific coactivator/lysine 
      acetyltransferase, Creb binding protein (CBP), and a specific deacetylase, 
      Sirtuin 1 (SIRT1). We recently reported that acetylation of HIF-2 by CBP also 
      requires a specific acetyl CoA generator, acetate-dependent acetyl CoA synthetase 
      2 (ACSS2). In this study, we demonstrate that ACSS2/HIF-2 signaling is active not 
      only during hypoxia, but also during glucose deprivation. Acetate levels increase 
      during stress and coincide with maximal HIF-2alpha acetylation and CBP/HIF-2alpha complex 
      formation. Exogenous acetate induces HIF-2alpha acetylation, CBP/HIF-2alpha complex 
      formation, and HIF-2 signaling. ACSS2 and HIF-2 are required for maximal colony 
      formation, proliferation, migration, and invasion during stress. Acetate also 
      stimulates flank tumor growth and metastasis in mice in an ACSS2 and HIF-2 
      dependent manner. Thus, ACSS2/CBP/SIRT1/HIF-2 signaling links nutrient sensing 
      and stress signaling with cancer growth and progression in mammals.
FAU - Chen, Rui
AU  - Chen R
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America; Key Laboratory of Environmental Medicine 
      Engineering, Ministry of Education, School of Public Health, Southeast 
      University, Nanjing, China.
FAU - Xu, Min
AU  - Xu M
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Nagati, Jason S
AU  - Nagati JS
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Hogg, Richard T
AU  - Hogg RT
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Das, Alok
AU  - Das A
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Gerard, Robert D
AU  - Gerard RD
AD  - Department of Molecular Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Garcia, Joseph A
AU  - Garcia JA
AD  - Department of Internal Medicine, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America; Department of Medicine, Veterans Affairs 
      North Texas Health Care System, Dallas, Texas, United States of America.
LA  - eng
GR  - I01 BX000446/BX/BLRD VA/United States
GR  - R01 HL108104/HL/NHLBI NIH HHS/United States
GR  - HL108104/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150217
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Acetates)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.3.1.48 (CREB-Binding Protein)
RN  - EC 2.3.1.48 (CREBBP protein, human)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - EC 6.2.1.1 (ACSS2 protein, human)
RN  - EC 6.2.1.1 (Acetate-CoA Ligase)
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
SB  - IM
EIN - PLoS One. 2015;10(3):e0123612. PMID: 25823015
MH  - Acetate-CoA Ligase/metabolism
MH  - Acetates/metabolism
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*metabolism
MH  - CREB-Binding Protein/metabolism
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Glucose/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Mice
MH  - Oxygen/metabolism
MH  - *Signal Transduction
MH  - Sirtuin 1/metabolism
MH  - *Tumor Microenvironment
PMC - PMC4331492
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/02/18 06:00
MHDA- 2016/02/24 06:00
PMCR- 2015/02/17
CRDT- 2015/02/18 06:00
PHST- 2014/09/25 00:00 [received]
PHST- 2014/12/10 00:00 [accepted]
PHST- 2015/02/18 06:00 [entrez]
PHST- 2015/02/18 06:00 [pubmed]
PHST- 2016/02/24 06:00 [medline]
PHST- 2015/02/17 00:00 [pmc-release]
AID - PONE-D-14-42884 [pii]
AID - 10.1371/journal.pone.0116515 [doi]
PST - epublish
SO  - PLoS One. 2015 Feb 17;10(2):e0116515. doi: 10.1371/journal.pone.0116515. 
      eCollection 2015.