Open AccessParadoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer
Author(s) -
María Teresa Gutiérrez-Salmerón,
José Manuel García-Martínez,
Javier MartínezUseros,
María Jesús Fernández-Aceñero,
Benoı̂t Viollet,
Séverine Olivier,
Jagat Chauhan,
Silvia Rocío Lucena,
Antonio De la Vieja,
Colin R. Goding,
Ana Chocarro-Calvo,
Custodia García-Jiménez
Publication year - 2020
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3000732
Subject(s) - biology , ampk , colorectal cancer , cancer research , medicine , microbiology and biotechnology , endocrinology , cancer , genetics , phosphorylation , protein kinase a
Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type–specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply–demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards β-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/β-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.