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The tRNA Gm18 Methyltransferase TARBP1 Promotes Hepatocellular Carcinoma Progression via Metabolic Reprogramming of Glutamine [Ribo-seq]

ABSTRACT: Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. In current study, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a novel driver gene critical for glutamine metabolic reprogramming in tumor through the CRISPRi/Cas9 screening. Our in vivo and in vitro assays demonstrated that TARBP1 is the methyltransferase of Guanosine 2'-O-methylation targeting position 18 (G18) of tRNAGln (TTG/CTG) and tRNASer (TGA/GCT), and loss of Gm18 modification diminishes the stability of tRNAs. Therefore, TARBP1 is critical for maintaining efficient translation of mRNA, in particular the glutamine transportor-ASCT2 (also known as SCL1A5). Importantly, TARBP1 is frequently amplified and overexpressed in HCC, consequentially promotes the protein synthesis of ASCT2 and glutamine import to fuel the growth of cancer cell, which is associated with poor patient survival. Taken together, this study reveals the critical role of TARBP1 in HCC progression through glutamine metabolic reprogramming and provides a potential target for tumor therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236366 | GEO | 2024/06/23

REPOSITORIES: GEO

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The tRNA Gm18 Methyltransferase TARBP1 Promotes Hepatocellular Carcinoma Progression via Metabolic Reprogramming of Glutamine [tRNA-seq]

Project description:Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. In current study, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a novel driver gene critical for glutamine metabolic reprogramming in tumor through the CRISPRi/Cas9 screening. Our in vivo and in vitro assays demonstrated that TARBP1 is the methyltransferase of Guanosine 2'-O-methylation targeting position 18 (G18) of tRNAGln (TTG/CTG) and tRNASer (TGA/GCT), and loss of Gm18 modification diminishes the stability of tRNAs. Therefore, TARBP1 is critical for maintaining efficient translation of mRNA, in particular the glutamine transportor-ASCT2 (also known as SCL1A5). Importantly, TARBP1 is frequently amplified and overexpressed in HCC, consequentially promotes the protein synthesis of ASCT2 and glutamine import to fuel the growth of cancer cell, which is associated with poor patient survival. Taken together, this study reveals the critical role of TARBP1 in HCC progression through glutamine metabolic reprogramming and provides a potential target for tumor therapy.

2024-06-23 | GSE236368 | GEO

ASCT2 is a major contributor to serine uptake in cancer cells

Project description:The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.

2024-06-11 | GSE269606 | GEO

IFRD1 promotes tumor cells “low-cost” survival under glutamine starvation via inhibiting histone H1.0 nucleophagy

Project description:Glutamine addiction represents a metabolic vulnerability of cancer cells although effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of IFRD1 (interferon-related developmental regulator 1) in the adaptive survival of hepatocellular carcinoma cells (HCC) during glutamine starvation. The induction and translocation of IFRD1 to the endoplasmic reticulum inhibits autophagy by promoting proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. On the contrary, enforced IFRD1 loss increases autophagy flux leading to cell death. This effect is largely realized through the autophagy-dependent degradation of histone H1.0 causing globally enhanced chromatin accessibility associated with unchecked increases in ribosome and protein biosynthesis . This in turn leads to metabolic exhaustion and death under glutamine starvation. Practically, IFRD1 depletion in preclinical HCC models potentiates glutamine limiting strategies including synergizing with the glutaminase-1 selective inhibitor CB-839. Thus, IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, with potential as a therapeutic target in anti-cancer applications.

2024-03-23 | GSE217406 | GEO

p53 promotes cancer cell adaptation to glutamine deprivation by upregulating Slc7a3 to increase arginine uptake

Project description:Cancer cells heavily depend on the amino acid, glutamine, to meet the demands associated with growth and proliferation. Due to its rapid consumption, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation using RNA-seq analysis. We show that Slc7a3, an arginine transporter, is significantly induced by p53. We show the concomitant rise in intracellular arginine levels following glutamine deprivation is dependent on p53. The influx of arginine has minimal effect on known metabolic pathways upon glutamine deprivation. Instead, we found arginine serves as an effector for mTORC1 activation to promote in vitro and in vivo cell growth in response to glutamine starvation. Therefore, we identify a novel p53-inducible gene that contributes to the metabolic stress response.

2019-05-15 | GSE125782 | GEO

Bach2 inhibits Th2-type immune responses by regulating glutamine metabolism [expression array]

Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.

2016-11-14 | GSE65083 | GEO

Bach2 inhibits Th2-type immune responses by regulating glutamine metabolism [ChIP-seq]

2016-11-14 | GSE63380 | GEO

NF1 deficiency drives metabolic reprogramming in ER+ breast cancer

Project description:NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies.

2023-12-25 | GSE251692 | GEO

MTR4 drives tumorigenesis of hepatocellular carcinoma by controlling alternative splicing of metabolic genes through PTBP1 recruitment

Project description:Aberrant alternative splicing (AS) is implicated in cancer metabolic reprogramming that supplies cancer cells with energy and substrates for biosynthesis. Therefore, the elucidation of the mechanism underlying aberrant AS in cancer cells is important for developing specific and effective therapy. We demonstrated that MTR4, a RNA helicase important for RNA quality surveillance, is frequently overexpressed in hepatocellular carcinoma (HCC) and is correlated with increased glycolysis and poor prognosis of HCC patients. MTR4 is required for tumorigenesis of HCC cells by promoting glycolysis and expression of glycolytic genes. MTR4 binds to specific motifs of pre-mRNAs, including those of the key glycolytic genes, and regulates their AS by recruiting PTBP1. We discovered that MTR4 is a direct transcriptional target of c-Myc, suggesting that MTR4 mediates the metabolic function of c-Myc in HCC. These findings reveal mechanisms driving cancer-specific AS profile and present MTR4 as a specific therapeutic target for treating HCC.

2019-12-17 | GSE129263 | GEO

O-GlcNAcylation enhances double strand break repair, promotes cancer cell proliferation and prevents therapy-induced senescence in irradiated tumors

Project description:The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism common in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein post-translational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double strand break (DSB) repair and resistance to therapy-induced senescence in cancer cells. Here, we have examined the effects of modulating O-GlcNAcylationon the DNA damage response in MCF7 human mammary carcinoma xenograft tumors. Promotingprotein O-GlcNAc modification, whether by targeting O-GlcNAcase (OGA) with shRNA or the inhibitor PUGNAc or simply treating animals with GlcNAc, protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by silencing O-GlcNActransferase (OGT) or treating animals with alloxan led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DNA damage response, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy.

2019-04-30 | PXD010820 | Pride

Pharmacological Induction of the Hypoxia Response Pathway in Huh7 Hepatoma Cells with Molidustat

Project description:The hypoxia response pathway enables adaptation to oxygen deprivation. It is mediated by hypoxia-inducible factors (HIF), which promote metabolic reprogramming, erythropoiesis, angiogenesis and tissue remodeling. This has led to the successful development of HIF-inducing drugs for treating anemia and some of these molecules have now reached the market. However, and because high levels of HIFs are frequently associated to tumor growth, poor prognosis and drug resistance in different types of cancer and in particular hepatocellular carcinoma (HCC), there is concerns that HIF-inducing drugs could promote cancer development. We therefore analyzed in detail the effects of the HIF-inducing drug Molidustat on Huh7 cells, a well-characterized HCC cell line. Combined transcriptomics, proteomics, metabolomics showed that Molidustat reduced cell proliferation, increased the expression of glycolytic enzymes and fragmented the mitochondrial network while decreasing cellular respiration. This profound metabolic remodeling was associated with an improved usage of pyruvate to overcome the inhibition of mitochondrial respiration, and a reduced dependence of this organelle on pyrimidine supply. Overall, this study shows that Molidustat increases the metabolic plasticity of Huh7 cells to adapt changes in their microenvironment, arguing for careful monitoring of patients treated with HIF-inducing drugs when at risk of HCC.

2024-07-30 | PXD049964 | Pride

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