Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor.
In aggressive, rapidly growing solid tumors such as glioblastoma multiforme (GBM), cancer cells face frequent dynamic changes in their microenvironment, including the availability of glucose and other nutrients. These challenges require that tumor cells have the ability to adapt in order to survive periods of nutrient/energy starvation. We have identified a reciprocal negative feedback loop mechanism in which the levels of microRNA-451 (miR-451) are negatively regulated through the phosphorylation and inactivation of its direct transcriptional activator OCT1 by 5' AMP-activated protein kinase (AMPK), which is activated by glucose depletion-induced metabolic stress. Conversely, in a glucose-rich environment, unrestrained expression of miR-451 suppresses AMPK pathway activity. These findings uncover miR-451 as a major effector of glucose-regulated AMPK signaling, allowing tumor cell adaptation to variations in nutrient availability in the tumor microenvironment.
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Khairul I
KI
Ansari
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurological Surgery, Kagawa University Hospital, Miki-cho, Kagawa 761-0793, Japan.
Daisuke
D
Ogawa
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Arun K
AK
Rooj
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sean E
SE
Lawler
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Anna M
AM
Krichevsky
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mark D
MD
Johnson
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
E Antonio
EA
Chiocca
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: abronisz@partners.org.
Agnieszka
A
Bronisz
Department of Neurosurgery, Harvey Cushing Neuro-oncology Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jgodlewski@partners.org.
Jakub
J
Godlewski
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
C531201:MIRN451 microRNA, human; D035683:MicroRNAs; C550758:Mirn451 microRNA, mouse; D050811:Octamer Transcription Factor-1; D055372:AMP-Activated Protein Kinases; D005947:Glucose