The survival rates for relapsed/refractory
acute lymphoblastic leukemia (ALL) remain poor. We and others have reported that ALL cells are vulnerable to conditions inducing energy/ER-stress mediated by
AMP-activated protein kinase (AMPK). To identify the target genes directly regulated by AMPKα2, we performed genome-wide
RNA-seq and ChIP-seq in CCRF-CEM (
T-ALL) cells expressing HA-AMPKα2 (CN2) under normal and energy/metabolic stress conditions. CN2 cells show significantly altered AMPKα2 genomic binding and transcriptomic profile under metabolic stress conditions, including reduced
histone gene expression. Proteomic analysis and in vitro
kinase assays identified the
TATA-Box-Binding Protein-Associated Factor 1 (TAF1) as a novel AMPKα2 substrate that downregulates
histone gene transcription in response to energy/metabolic stress. Knockdown and knockout studies demonstrated that both AMPKα2 and TAF1 are required for
histone gene expression. Mechanistically, upon activation, AMPKα2 phosphorylates TAF1 at Ser-1353 which impairs TAF1 interaction with
RNA polymerase II (Pol II), leading to a compromised state of p-AMPKα2/p-TAF1/Pol II
chromatin association and suppression of transcription. This mechanism was also observed in primary ALL cells and in vivo in NSG mice. Consequently, we uncovered a non-canonical function of AMPK that phosphorylates TAF1, both members of a putative
chromatin-associated transcription complex that regulate
histone gene expression, among others, in response to energy/metabolic stress.
IMPLICATIONS: Fully delineating the
protein interactome by which AMPK regulates adaptive survival responses to energy/metabolic stress, either via epigenetic gene regulation or other mechanisms, will allow the rational development of strategies to overcome de novo or acquired resistance in ALL and other
cancers.