Both enzymatic and non-enzymatic functions of BCAT1 confer malignant properties in human chondrosarcoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303334 | GEO | 2026/01/01
REPOSITORIES: GEO
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Project description:Both enzymatic and non-enzymatic functions of BCAT1 confer malignant properties in human chondrosarcoma
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Project description:High levels of branched-chain amino acid (BCAA) transaminase 1 (Bcat1) have been associated with adverse prognosis and drug resistance in several cancer types. However, the mechanistic role of Bcat1 in T-cell acute lymphoblastic leukemia (T-ALL) development is ill defined.We determined the effects of BCAT1 depletion on cellular sensitivity to DNA damaging agents (etoposide).
2025-01-02 | GSE275161 | GEO
Project description:Previously, we have identified cytosolic form of the branched chain amino-acid transaminase 1 (BCAT1) as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in BCAT1 overexpression in serous epithelial ovarian cancer (EOC). Knockdown of the BCAT1 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, BCAT1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon BCAT1 suppression, while some tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the BCAT1 gene in advanced EOC and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.
2015-10-01 | GSE64424 | GEO
Project description:In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABLT315I-induced murine TKI-resistant CML model . Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro.
2024-05-30 | GSE262421 | GEO
Project description:Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) is a metabolic enzyme that converts branched-chain amino acids into branched-chain keto acids, depleting cellular α-ketoglutarate and producing glutamate. BCAT1 was shown to drive the growth of glioblastoma and other cancers; however, its oncogenic mechanism remains poorly understood. Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of TET demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8 + cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. In summary, our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.
2024-11-08 | GSE247299 | GEO
Project description:High levels of branched-chain amino acid (BCAA) transaminase 1 (Bcat1) have been associated with adverse prognosis and drug resistance in several cancer types. However, the mechanistic role of Bcat1 in T-cell acute lymphoblastic leukemia (T-ALL) development is ill defined. Here, we used a mouse T-ALL model to show that Bcat1 is required for T-ALL development and maintenance. Using a NOTCH1 gain-of-function retroviral model of T-ALL, mouse cells genetically deficient for Bcat1 showed defects in developing leukemia. Amongst the pathways upregulated in Bcat1 KO delta E-NOTCH1 cells we found “DNA repair”, “apoptosis”, and “p53 pathway”. We thus hypothesize that Bcat1 may be implicated in cell cycle progression or apoptosis of T-ALL cells.
2024-09-01 | GSE267966 | GEO
Project description:Neuroblastoma (NB) is a common neuroendocrine tumor in early childhood, and the poor prognosis of high-risk NB is due to its poorly differentiated characteristics and immunosuppressive microenvironment. Around 25% of high-risk NB in children is caused by MYCN gene amplification. In this study, we found that Branched-chain amino acid transaminase 1 (BCAT1) is overexpressed in NB, especially those with MYCN amplification, and is a positively correlated with MYCN expression. Moreover, BCAT1 may be a risk factor for NB, significantly affecting proliferation of NB cells. Besides, we revealed that MYCN directly regulated BCAT1 transcription through binding to BCAT1 promoter, thus enhancing BCAT1-MYCN cooperativity. The highly disordered loop region of the MYCN protein makes it readily degraded under natural conditions, making it difficult to obtain the real structure of MYCN through experiments. We performed GROMACs optimization on the MYCN structure obtained from Alphafold, which increased the reliability of the MYCN structure and met the requirements of subsequent protein docking experiments. In this study, we found that after BCAT1 binds to the disordered regions of MYCN, it can improve the overall stability of MYCN. Therefore, we hypothesized that BCAT1 can enhance the stability of MYCN, suggesting that BCAT1 may be a potential therapeutic target for MYCN-amplified NB. In summary, these findings establish BCAT1 is a critical oncogenic factor in NB and provide a new potential target for treatment of NB with MYCN amplification.
2025-04-01 | GSE267875 | GEO
Project description:Role of Branched Chain Amino Acid Transaminase 1 (BCAT1) in Acute Myeloid Leukemia
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Project description:The branched chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. By performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem cell (LSC) and non-LSC populations, we found the BCAA pathway enriched and BCAT1 overexpressed in LSCs. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Next to its role in the tricarboxylic acid (TCA) cycle αKG is an essential co-factor for αKG-dependent dioxygenases such as EGLN1 and the TET family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG leading to HIF1a protein degradation mediated by EGLN1. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. In contrast, overexpression (OE) of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation via altered TET activity. BCAT1high AMLs displayed a DNA hypermethylation phenotype similar to cases carrying mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHwtTET2wt, but not IDHmut or TET2mut AMLs. Gene sets characteristic for IDHmut AMLs were enriched in IDHwtTETwtBCAT1high patient samples. BCAT1high AMLs showed robust enrichment for LSC signatures and paired sample analysis revealed a significant increase of BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1a stability and regulation of the epigenomic landscape. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise LSC function in IDHwtTET2wt AML patients.
2017-11-08 | GSE100783 | GEO
Project description:The branched chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. By performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem cell (LSC) and non-LSC populations, we found the BCAA pathway enriched and BCAT1 overexpressed in LSCs. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Next to its role in the tricarboxylic acid (TCA) cycle αKG is an essential co-factor for αKG-dependent dioxygenases such as EGLN1 and the TET family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG leading to HIF1a protein degradation mediated by EGLN1. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. In contrast, overexpression (OE) of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation via altered TET activity. BCAT1high AMLs displayed a DNA hypermethylation phenotype similar to cases carrying mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHwtTET2wt, but not IDHmut or TET2mut AMLs. Gene sets characteristic for IDHmut AMLs were enriched in IDHwtTETwtBCAT1high patient samples. BCAT1high AMLs showed robust enrichment for LSC signatures and paired sample analysis revealed a significant increase of BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1a stability and regulation of the epigenomic landscape. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise LSC function in IDHwtTET2wt AML patients.
2017-11-08 | GSE100782 | GEO