Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer.
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-a...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-06-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3000732 |
| _version_ | 1818589163697471488 |
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| author | María Gutiérrez-Salmerón José Manuel García-Martínez Javier Martínez-Useros María Jesús Fernández-Aceñero Benoit Viollet Severine Olivier Jagat Chauhan Silvia R Lucena Antonio De la Vieja Colin R Goding Ana Chocarro-Calvo Custodia García-Jiménez |
| author_facet | María Gutiérrez-Salmerón José Manuel García-Martínez Javier Martínez-Useros María Jesús Fernández-Aceñero Benoit Viollet Severine Olivier Jagat Chauhan Silvia R Lucena Antonio De la Vieja Colin R Goding Ana Chocarro-Calvo Custodia García-Jiménez |
| author_sort | María Gutiérrez-Salmerón |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T09:36:17Z |
| format | Article |
| id | doaj.art-d6b95076bfc94e6c82999824a59bfd60 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-16T09:36:17Z |
| publishDate | 2020-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-d6b95076bfc94e6c82999824a59bfd602022-12-21T22:36:24ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852020-06-01186e300073210.1371/journal.pbio.3000732Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer.María Gutiérrez-SalmerónJosé Manuel García-MartínezJavier Martínez-UserosMaría Jesús Fernández-AceñeroBenoit ViolletSeverine OlivierJagat ChauhanSilvia R LucenaAntonio De la ViejaColin R GodingAna Chocarro-CalvoCustodia García-JiménezCoordination 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.https://doi.org/10.1371/journal.pbio.3000732 |
| spellingShingle | María Gutiérrez-Salmerón José Manuel García-Martínez Javier Martínez-Useros María Jesús Fernández-Aceñero Benoit Viollet Severine Olivier Jagat Chauhan Silvia R Lucena Antonio De la Vieja Colin R Goding Ana Chocarro-Calvo Custodia García-Jiménez Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. PLoS Biology |
| title | Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. |
| title_full | Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. |
| title_fullStr | Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. |
| title_full_unstemmed | Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. |
| title_short | Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer. |
| title_sort | paradoxical activation of ampk by glucose drives selective ep300 activity in colorectal cancer |
| url | https://doi.org/10.1371/journal.pbio.3000732 |
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