Expression of GOT2 Is Epigenetically Regulated by DNA Methylation and Correlates with Immune Infiltrates in Clear-Cell Renal Cell Carcinoma

Ferreira, Wallax Augusto Silva; Oliveira, Edivaldo Herculano Corrêa de

doi:10.3390/cimb44060169

Cited by 9 publications

(11 citation statements)

References 77 publications

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“…We selected three single-cell RNA-seq (scRNA-seq) datasets: (i) the GSE132509 dataset 33 , which consisted of 37,936 cells from 11 childhood acute lymphoblastic leukemia (cALL) patients (8 cALL patients with > 50% blasts and three healthy donors); (ii) the GSE153697 dataset 34 , which included 2,904 cells from one child diagnosed with B-ALL and treated with anti-CD19 CAR-T therapy; and (iii) GSE154109 dataset 35 comprising 10,800 cells from seven pediatric patients with B-ALL. We downloaded and analyzed these datasets according to the methods previously described [72][73][74] .…”

Section: Single-cell Sequencing Analysismentioning

confidence: 99%

PARP1 is differentially expressed in BCR-ABL p190+ ALL patient samples and targeting PARP inhibition induces cell death comparable to that of tyrosine- kinase golden standard in pre-clinical models

Machado

Silva

Ferreira

et al. 2023

Preprint

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Detection of t(9;22), and consequent BCR-ABL1 fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model of BCR-ABL p190 + ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current golden-standard in medical care. We characterized cytostatic profiles, induced cell death and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190 + patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in the clinical practice.

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Section: Single-cell Sequencing Analysismentioning

confidence: 99%

PARP1 is differentially expressed in BCR-ABL p190+ ALL patient samples and targeting PARP inhibition induces cell death comparable to that of tyrosine- kinase golden standard in pre-clinical models

Machado

Silva

Ferreira

et al. 2023

Preprint

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“…For example, GOT2 can traffic fatty acids leading to suppression of antitumor immunity via the peroxisome proliferator activated receptor alpha-dependent pathway (PPAR) 45,46 . In triple negative breast cancer, GOT2 overexpression was associated with increased proliferation 47–49 , while in clear cell renal cell carcinoma GOT2 was downregulated and associated with poor survival and immune infiltrates 50 . A gain of function mutation in GOT2 has been reported in rare neurological tumors that also harbor loss of function mutations in the malate aspartate shuttle 51,52 .…”

Section: Introductionmentioning

confidence: 98%

Pan-cancer molecular signatures connecting aspartate transaminase (AST) to cancer prognosis, metabolic and immune signatures

Siwo,

Singal,

Waljee

2024

Preprint

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Background: Serum aspartate transaminase (sAST) level is used routinely in conjunction with other clinical assays to assess liver health and disease. Increasing evidence suggests that sAST is associated with all-cause mortality and has prognostic value in several cancers, including gastrointestinal and urothelial cancers. Here, we undertake a systems approach to unravel molecular connections between AST and cancer prognosis, metabolism, and immune signatures at the transcriptomic and proteomic levels. Methods: We mined public gene expression data across multiple normal and cancerous tissues using the Genotype Tissue Expression (GTEX) resource and The Cancer Genome Atlas (TCGA) to assess the expression of genes encoding AST isoenzymes (GOT1 and GOT2) and their association with disease prognosis and immune infiltration signatures across multiple tumors. We examined the associations between AST and previously reported pan-cancer molecular subtypes characterized by distinct metabolic and immune signatures. We analyzed human protein-protein interaction networks for interactions between GOT1 and GOT2 with cancer-associated proteins. Using public databases and protein-protein interaction networks, we determined whether the subset of proteins that interact with AST (GOT1 and GOT2 interactomes) are enriched with proteins associated with specific diseases, miRNAs and transcription factors. Results: We show that AST transcript isoforms (GOT1 and GOT2) are expressed across a wide range of normal tissues. AST isoforms are upregulated in tumors of the breast, lung, uterus, and thymus relative to normal tissues but downregulated in tumors of the liver, colon, brain, kidney and skeletal sarcomas. At the proteomic level, we find that the expression of AST is associated with distinct pan-cancer molecular subtypes with an enrichment of specific metabolic and immune signatures. Based on human protein-protein interaction data, AST physically interacts with multiple proteins involved in tumor initiation, suppression, progression, and treatment. We find enrichments in the AST interactomes for proteins associated with liver and lung cancer and dermatologic diseases. At the regulatory level, the GOT1 interactome is enriched with the targets of cancer-associated miRNAs, specifically mir34a - a promising cancer therapeutic, while the GOT2 interactome is enriched with proteins that interact with cancer-associated transcription factors. Conclusions: Our findings suggest that perturbations in the levels of AST within specific tissues reflect pathophysiological changes beyond tissue damage and have implications for cancer metabolism, immune infiltration, prognosis, and treatment personalization.

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“…GOT2 can also inhibit antitumor immunity by shaping the immune microenvironment through spatially limiting both CD4 + and CD8 + T cells [ 38 ]. High GOT2 expression is positively associated with immunologically quiet subtype patients and can be used for clear-cell renal cell carcinoma immunophenotyping as a marker [ 39 ]. Nevertheless, the potential molecular mechanisms of GLS and GOT2 in breast cancer have yet to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

GLS and GOT2 as prognostic biomarkers associated with dendritic cell and immunotherapy response in breast cancer

Yang,

Cheng,

Xiao

et al. 2024

Heliyon

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Expression of GOT2 Is Epigenetically Regulated by DNA Methylation and Correlates with Immune Infiltrates in Clear-Cell Renal Cell Carcinoma

Cited by 9 publications

References 77 publications

PARP1 is differentially expressed in BCR-ABL p190+ ALL patient samples and targeting PARP inhibition induces cell death comparable to that of tyrosine- kinase golden standard in pre-clinical models

PARP1 is differentially expressed in BCR-ABL p190+ ALL patient samples and targeting PARP inhibition induces cell death comparable to that of tyrosine- kinase golden standard in pre-clinical models

Pan-cancer molecular signatures connecting aspartate transaminase (AST) to cancer prognosis, metabolic and immune signatures

GLS and GOT2 as prognostic biomarkers associated with dendritic cell and immunotherapy response in breast cancer

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