The NF-κB member p65 controls glutamine metabolism through miR-23a.
Cancer cells have elevated aerobic glycolysis that is termed the Warburg effect. But several tumor cells, including leukemic cells, also increase glutamine metabolism, which is initiated by glutaminase (GLS). The microRNA (miRNA) miR-23 targets GLS mRNA and inhibits expression of GLS protein. Here we show that in human leukemic Jurkat cells the NF-κB p65 subunit binds to miR-23a promoter and inhibits miR-23a expression. Histone deacetylase (HDAC) inhibitors release p65-induced inhibition. Jurkat cells growing in glutamine decrease proliferation due to cell accumulation in G0/G1 phase. Nevertheless, cells get used to this new source of energy by increasing GLS expression, which correlates with an increase in p65 expression and its translocation to the nucleus, leading to a higher basal NF-κB activity. Jurkat cells overexpressing p65 show increase basal GLS expression and proliferate faster than control cells in glutamine medium. Overexpressing miR-23a in leukemic cells impaired glutamine use and induces mitochondrial dysfunction leading to cell death. Therefore, p65 activation decreases miR-23a expression, which facilitates glutamine consumption allowing leukemic cells to use this alternative source of carbon and favoring their adaptation to the metabolic environment.
INSERM, U1040, Montpellier, France.
Moeez G
MG
Rathore
Anne
A
Saumet
Jean-François
JF
Rossi
Carine
C
de Bettignies
Denis
D
Tempé
Charles-Henri
CH
Lecellier
Martin
M
Villalba
D000818:Animals; D001483:Base Sequence; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; D051996:Transcription Factor RelA; D005973:Glutamine; D008156:Luciferases; D005972:Glutaminase; D006655:Histone Deacetylases