Effect of G6PD loss on gene expression in LKB1 deficient KRAS-driven lung tumor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1066355 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27638379_1.fastq.gz | Fastqsanger.gz | |||
| SRR27638379_2.fastq.gz | Fastqsanger.gz | |||
| SRR27638380_1.fastq.gz | Fastqsanger.gz | |||
| SRR27638380_2.fastq.gz | Fastqsanger.gz | |||
| SRR27638381_1.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cells heavily rely on nicotinamide adenine dinucleotide phosphate (NADPH) to counteract oxidative stress and facilitate reductive biosynthesis. One crucial route for NADPH production operates through the oxidative pentose phosphate pathway, with a pivotal step at glucose-6-phosphate dehydrogenase (G6PD). This study delves into the repercussions of G6PD ablation on the development of lung tumors driven by the KRAS oncogene and deficient in LKB1 (KL). The research involved comparing the growth of KL lung tumors with or without G6PD, revealing a significant inhibition of KL lung tumor growth upon G6PD loss. Subsequently, RNA-seq analysis was employed to identify the alterations in gene expression following G6PD deletion, providing insights into the underlying mechanisms.
2024-01-23 | GSE253613 | GEO
Project description:Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;p53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.
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Project description:Investigate how loss of Lkb1 in the context of KRAS mutation alters metablism in cancer and contributes in cancer aggressiveness
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Project description:LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation during tumor development and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and promoted tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove the transition of neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth. Thus, we uncover a role for a critical tumor suppressor in the regulation of key lineage-specific transcription factors, thereby constraining lung tumor development through the enforcement of differentiation.
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Project description:Intermediary metabolism generates substrates for covalent modification of chromatin, enabling potential coupling of metabolic states and epigenetic control. Here, we identify such a network as a major component of oncogenic transformation downstream of the LKB1 tumour suppressor. LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, however the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing genetically engineered mouse and primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced mTOR-dependent induction of the serine-glycine-one carbon network coupled to S-adenosylmethionine generation. In concert, DNA methyltransferases (DNMT1, DNMT3A) are upregulated, leading to elevation in genomic 5-methylcytosine levels, with particular enrichment at retrotransposon elements, associated with silencing of retrotransposon transcription. Correspondingly, LKB1 deficiency renders cells highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from LKB1 loss and KRAS activation that fuels changes in the epigenetic landscape. This state is critically required for the tumourigenic program of LKB1-mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets.
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Project description:Intermediary metabolism generates substrates for covalent modification of chromatin, enabling potential coupling of metabolic states and epigenetic control. Here, we identify such a network as a major component of oncogenic transformation downstream of the LKB1 tumour suppressor. LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, however the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing genetically engineered mouse and primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced mTOR-dependent induction of the serine-glycine-one carbon network coupled to S-adenosylmethionine generation. In concert, DNA methyltransferases (DNMT1, DNMT3A) are upregulated, leading to elevation in genomic 5-methylcytosine levels, with particular enrichment at retrotransposon elements, associated with silencing of retrotransposon transcription. Correspondingly, LKB1 deficiency renders cells highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from LKB1 loss and KRAS activation that fuels changes in the epigenetic landscape. This state is critically required for the tumourigenic program of LKB1-mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets.
2016-10-24 | GSE86143 | GEO
Project description:Excessive glucose production in the liver is a key factor in the hyperglycemia observed in diabetes mellitus type 2. It is generally agreed to result from an increase in hepatic gluconeogenesis. Considerable attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, but much less is known about the regulation of amino-acid catabolism, which generates gluconeogenic substrates. Here, we highlight a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect was observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion was associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and specifically, Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis. The present dataset is from the phosphoproteomic analysis of fasting mice in a study where a global quantitative analysis ( PXD013478 ) is also described in the same publication.
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Project description:Excessive glucose production in the liver is a key factor in the hyperglycemia observed in diabetes mellitus type 2. It is generally agreed to result from an increase in hepatic gluconeogenesis. Considerable attention has been devoted to the transcriptional regulation of key gluconeogenic enzymes, but much less is known about the regulation of amino-acid catabolism, which generates gluconeogenic substrates. Here, we highlight a novel role of LKB1 in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect was observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion was associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic and pharmacological approaches, we identified the aminotransferases and specifically, Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis. The present dataset is from the phosphoproteomic analysis of the refed mice in a study where a global quantitative analysis ( PXD013478 ) is also described in the same publication.
2020-12-01 | PXD019755 | Pride
Project description:Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
2025-05-07 | PXD052379 | Pride
Project description:Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
2025-05-06 | PXD051954 | Pride