ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression

Abstract

The c-Myc oncogene (MYC) drives malignant progression, but also induces robust anabolic and proliferative programs leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. We have uncovered an essential role for the transcription factor ATF4 in survival following MYC activation. MYC upregulates ATF4 by activating GCN2 kinase through uncharged tRNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC target genes, primarily those regulating amino acid and protein synthesis, including 4E-BP1, a negative regulator of translation. 4E-BP1 is essential to balance protein synthesis, relieving MYC-induced proteotoxic stress. 4E-BP1 activity is negatively regulated by mTORC1-dependent phosphorylation and inhibition of mTORC1 signaling rescues ATF4 deficient cells from MYC-induced ER stress. Acute deletion of ATF4 significantly delays MYC-driven tumor progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC-activity, ensuring enhanced translation rates are compatible with survival and tumor progression.

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

“…upregulated glycolytic and downregulated TCA cycle activity leading to consequent reduction in inflammatory cytokine production and anergy- are best explained by the observed H3K27 mediated silencing of key transcription factors such as MYC, PPARg and PPRC1 as a consequence of GSK-J4 treatment (61). Recently, it has been shown that inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress (60). This reveals an essential role for ATF4 in survival following MYC activation and our data suggests that KDM demethylases are an important regulator of this pathway.…”

Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program

“…In this methionine--dependent context, cells co-opt Gcn4, which is conventionally viewed as a 'survival/stress' transcription factor, to provide this supply of metabolic precursors. Relevantly, recent studies of the mammalian ortholog of Gcn4 (ATF4) now report high ATF4 activity in several cancers (Pällmann et al, 2019;Singleton and Harris, 2012;Tameire et al, 2019;Ye et al, 2010). These studies suggest that ATF4 induction is critical for tumor progression during nutrient limitation, possibly by providing otherwise limiting metabolites (Tameire et al, 2019;Ye et al, 2010).…”

“…Relevantly, recent studies of the mammalian ortholog of Gcn4 (ATF4) now report high ATF4 activity in several cancers (Pällmann et al, 2019;Singleton and Harris, 2012;Tameire et al, 2019;Ye et al, 2010). These studies suggest that ATF4 induction is critical for tumor progression during nutrient limitation, possibly by providing otherwise limiting metabolites (Tameire et al, 2019;Ye et al, 2010). Separately, observations over decades note that many tumors depend on sulfur amino acids, especially methionine (Breillout et al, 1990;Poirson--Bichat et al, 2000), and methionine restriction critically determines tumor progression (Gao et al, 2019b(Gao et al, , 2019a.…”

Methylated PP2A stabilizes Gcn4 to enable a methionine-induced anabolic program

“…Although it is primarily studied in the context of starvation, during a methionine driven growth program Gcn4 activity fuels the synthesis of required biosynthetic precursors to drive growth. Interestingly, such scenarios are also observed in several tumors, where the mammalian ortholog of Gcn4 (ATF4) is induced and helps in tumor proliferation (57)(58)(59)(60). The mechanisms of induction of ATF4 in these contexts have not been well studied, and the mechanism observed in this study is plausible in those contexts of high growth.…”