Open AccessThe Acetate/ACSS2 Switch Regulates HIF-2 Stress Signaling in the Tumor Cell Microenvironment
Author(s) -
Rui Chen,
Min Xu,
Jason S. Nagati,
Richard T. Hogg,
Alok Kumar Das,
Robert D. Gerard,
Joseph A. Garcia
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0116515
Subject(s) - acetylation , creb binding protein , microbiology and biotechnology , sirtuin , cell growth , signal transduction , chemistry , p300 cbp transcription factors , sirtuin 1 , acetyltransferase , creb , biology , biochemistry , downregulation and upregulation , transcription factor , gene , histone acetyltransferases
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-2α acetylation and CBP/HIF-2α complex formation. Exogenous acetate induces HIF-2α acetylation, CBP/HIF-2α 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.