Translational activation of ATF4 through mitochondrial anaplerotic metabolic pathways is required for DLBCL growth and survival
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA666669 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12748700.fastq.gz | Fastqsanger.gz | |||
| SRR12748701.fastq.gz | Fastqsanger.gz | |||
| SRR12748702.fastq.gz | Fastqsanger.gz | |||
| SRR12748703.fastq.gz | Fastqsanger.gz | |||
| SRR12748704.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cells frequently hijack adaptive stress response signals/pathways to protect themselves from metabolic or genetic vulnerabilities, pointing to candidate therapeutic targets. Among these SIRT3 was recently identified as a non-oncogene addiction mechanism in DLBCL through its role in glutamine metabolism. Here, we investigated downstream signaling pathways linked to SIRT3 function in lymphoma. We performed RNA-seq in DLBCL cells after SIRT3 knockdown and observed that ATF4 target genes were significantly downregulated in SIRT3 deficient cells. ATF4, a master regulator of cellular stress, was required to maintain proliferation and survival of DLBCL cells and its target genes were overexpressed in DLBCL patients as compared to normal germinal center B cells. Translation of ATF4 mRNA was inhibited in SIRT3 knockdown cells and expression of exogenous ATF4 partially rescued cell proliferation and viability inhibited by SIRT3 deficiency. Accordingly, ATF4 protein was expressed at relatively lower levels SIRT3 deficient murine lymphomas, whereas its higher expression was associated with more severe disease. We characterized mechanisms through which SIRT3 maintains ATF4 expression, downstream of its effects on glutamine entry into the TCA cycle and suppression of autophagy. Specifically, loss of SIRT3 disrupted amino acid metabolism in DLBCL cells, with subsequent impairment of ATF4 response to metabolic stressors such as glutamine depletion. Collectively, the data suggest a key SIRT3-ATF4 axis maintains survival of DLBCL cells enabling them to optimize amino acid metabolism and cope with metabolic vulnerabilities possibly associated with their high proliferative rate.
2022-09-20 | GSE158833 | GEO
Project description:Diffuse large B-cell lymphomas (DLBCL) are broadly dependent on anaplerotic metabolism regulated by mitochondrial SIRT3. Herein we find that translational upregulation of ATF4 is coupled with anaplerotic metabolism in DLBCLs due to nutrient deprivation caused by SIRT3 driving rapid flux of glutamine into the tricarboxylic acid (TCA) cycle. SIRT3 depletion led to ATF4 downregulation and cell death, which was rescued by ectopic ATF4 expression. Mechanistically, ATF4 translation is inhibited in SIRT3-deficient cells due to the increased pools of amino acids derived from compensatory autophagy and decreased glutamine consumption by the TCA cycle. Absence of ATF4 further aggravates this state through downregulation of its target genes, including genes for amino acid biosynthesis and import. Collectively, we identify a SIRT3-ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimize amino acid uptake and utilization. Targeting ATF4 translation can potentiate the cytotoxic effect of SIRT3 inhibitor to DLBCL cells. SIGNIFICANCE: We discovered the link between SIRT3 and ATF4 in DLBCL cells, which connected lymphoma amino acid metabolism with ATF4 translation via metabolic stress signals. SIRT3-ATF4 axis is required in DLBCL cells regardless of subtype, which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target.This article is highlighted in the In This Issue feature, p. 1.
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Project description:Dysregulation of the proto-oncogene c-Myc (MYC henceforward) 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 cell 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, including those regulating amino acid biosynthesis/transport and protein synthesis. ATF4 is essential for MYC-induced upregulation of the negative translational regulator and mTOR target 4E-BP1 and genetic or pharmacological inhibition of mTOR signaling rescues ATF4 deficient cells from MYC-induced 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.
2018-07-18 | GSE117240 | GEO
Project description:Cells adapt to proteostatic and metabolic stresses, in part, by triggering the phosphorylation of eIF2alpha and the subsequent synthesis of ATF4. eIF2alpha phosphorylation facilitates translational induction of ATF4 by regulating reinitiation of the scanning ribosomes at the ATF4 mRNA’s 5’ leader. In addition to eIF2alpha, ATF4 induction requires other regulators that remain poorly understood. Here, we report an ATF4 regulatory network consisting of eIF4E-Homologous Protein (4EHP), NELF-E, the 40S ribosome, and eIF3 subunits. Specifically, 4EHP was required for ATF4 signaling in the Drosophila larval fat body and in disease models associated with abnormal ATF4 signaling. 4EHP’s mRNA cap-binding domain specifically interacted with NELF-E mRNA, which encodes a regulator of pol II-mediated transcription. Both NELF-E and 4EHP were required for the expression of ATF4 and enzymes that mediate the serine-one-carbon pathway. Knockdown of NELF-E also reduced several subunits of the 40S ribosome and the eIF3 translation initiation factor complex. Reduction of Rps12 and eif3h suppressed physiological ATF4 induction. These results uncover a previously unrecognized ATF4 regulatory network that impacts stress adaptation and pathological outcomes.
2025-11-19 | GSE309407 | GEO
Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2α, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2α/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2α S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2α phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2α, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.
2016-07-03 | E-GEOD-68265 | biostudies-arrayexpress
Project description:Germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is one of the most common subtypes of B-cell non-Hodgkin lymphoma. The tumor microenvironment (TME) is responsible for therapy resistance and relapse in GCB-DLBCL, while most studies have focused on targeting tumor cells instead of the TME. Stromal cells are the main component of the TME in GCB-DLBCL. How stromal cells interact with GCB-DLBCL tumor cells and protect GCB-DLBCL from cell death remain elusive. Here we reported that a CD40/RANK pathway-mediated positive feedback loop mediated the interaction of stromal cells and GCB-DLBCL to enhance the survival of GCB-DLBCL tumor cells. The viability of primary GCB-DLBCL patient-derived xenograft tumor cells was increased when they were cocultured with different tissue-derived stromal cells. We demonstrated that stromal cells promoted tumor cell survival not only through excreted cytokines but also depending more on direct contact. Furthermore, CD40 ligand (CD40L) expressed on stromal cells activated CD40 signaling in tumor cells, protecting tumor cells from apoptosis and upregulating RANK ligand (RANKL). RANK activation by RANKL in tumor cells enhanced the expression of CD40L and BAFF in stromal cells, both of which in turn promoted tumor cell survival through activating canonical and noncanonical NF-B signaling. In addition, CD40 activation upregulated the expression of KDM6B, and KDM6B further mediated the activation of canonical and noncanonical NF-B signaling, the downstream signaling pathways of the CD40 activation, all leading to tumor cell survival. These results further suggest that CD40-KDM6B-NF-B axis serve as a potential target for GCB-DLBCL therapy.
2022-05-09 | GSE202370 | GEO
Project description:Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. To identify ATF4 target genes that mediate the ISR outcome and to get insight into its mechanism of action in PCa, we performed global proteomic expression profiling in parallel with transcriptomic expression profiling. These data show that ATF4 regulates important metabolic pathways in PCa cells.
2019-07-22 | PXD012858 | Pride
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2025-04-22 | GSE273595 | GEO
Project description:High expression of the FOXP1 transcription factor distinguishes the highly aggressive Activated B Cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL) from the more indolent Germinal Center (GCB) DLBCL subtype and is correlated with poor prognosis. A genetic or functional role for FOXP1 in lymphomagenesis and/or tumor maintenance, however, remains unknown. Here, we report that sustained expression of FOXP1 is necessary for ABC DLBCL cell line survival. Genome-wide transcript profiling reveals that FOXP1 acts directly and indirectly by enforcing expression of known ABC DLBCL hallmarks, including the classical NF-kappaB survival pathway. Our data further suggest that FOXP1 maintains the ABC subtype distinction by repressing gene expression programs dominant in GCB DLBCL and supports a model in which the target of ABC DLBCL transformation is a transitory cell type en route from the germinal center B cell to the terminally differentiated plasma cell.
2015-12-01 | GSE64586 | GEO