Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression

Yang, Dongdong; Liu, Haiying; Cai, Yongping; Lu, Kangyang; Zhong, Xiuying; Xing, Songge; Song, Wei; Zhang, Yaping; Ye, Ling; Zhu, Xiongwei; Wang, Ting; Zhang, Pinggen; Li, Shiting; Feng, Jiaqian; Jia, Weidong; Zhang, Huafeng; Gao, Peng

doi:10.1016/j.celrep.2022.111691

Cited by 19 publications

(12 citation statements)

References 40 publications

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“…The supplement of palmitic acid could robustly rescue the impaired cell proliferation caused by BCKDHA deficiency. Apart from this, another investigation employed by Yang et al has revealed that in response to glutamine deprivation, the activity of BCKDHA was enhanced due to dephosphorylation by PPM1K, which ensured the biogenesis of nucleotides and thereby cell‐cycle progression 16 . In this regard, BCKDHA seems to act as a lethal partner under the circumstance of glutamine shortage, and the combined suppression of both BCKDHA and glutamine metabolism has been proved as a useful therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from this, another investigation employed by Yang et al has revealed that in response to glutamine deprivation, the activity of BCKDHA was enhanced due to dephosphorylation by PPM1K, which ensured the biogenesis of nucleotides and thereby cell-cycle progression. 16 In this regard, BCKDHA seems to act as a lethal partner under the circumstance of glutamine shortage, and the combined suppression of both BCKDHA and glutamine metabolism has been proved as a useful therapeutic strategy. In line with the result in PDAC, our data which can phosphorylate BCKDHA and suppress its activity is also the upstream kinase of ACLY.…”

Section: Discussionmentioning

confidence: 99%

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BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

Tian

Wang

et al. 2023

Experimental Dermatology

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The dysregulation of branched‐chain amino acid (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Here, we explored the role of the BCAA metabolism enzyme BCKDHA in melanoma pathogenesis and elucidated the underlying mechanisms. In vitro cell biology experiments and in vivo pre‐clinical mice model experiments were performed to investigate the role of BCKDHA in melanoma progression. RNA sequencing, immunohistochemical/immunofluorescence staining and bioinformatics analysis were used to examine the underlying mechanism. BCKDHA expression was prominently increased in both melanoma tissues and cell lines. The up‐regulation of BCKDHA promoted long‐term tumour cell proliferation, invasion and migration in vitro and tumour growth in vivo. Through RNA‐sequencing technology, it was found that BCKDHA regulated the expressions of lipogenic fatty acid synthase (FASN) and ATP‐citrate lyase (ACLY), which was thereafter proved to mediate the oncogenic role of BCKDHA in melanoma. Our results demonstrate that BCKDHA promotes melanoma progression by regulating FASN and ACLY expressions. Targeting BCKDHA could be exploited as a promising strategy to restrain tumour progression in melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

Tian

Wang

et al. 2023

Experimental Dermatology

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“…Furthermore, cellular metabolism also exerts an influence on the level of O-GlcNAc; for example, a deficiency in glutamine can significantly elevate O-GlcNAc levels. 54 Nevertheless, it remains unclear whether alterations in metabolic levels contribute to the observed increase in O-GlcNAc levels during pmr1 knockout. In general, the deletion of pmr1 may exert an influence on protein glycosylation through its regulation of intracellular Mn 2+ and Ca 2+ levels, post-transcriptional translation, and intracellular metabolism.…”

Section: ■ Discussionmentioning

confidence: 99%

“…O-GlcNAc Transferase (OGT) is a crucial enzyme responsible for catalyzing the attachment of N-acetylglucosamine molecules to hydroxyl amino acids on proteins, thereby facilitating the formation of O-GlcNAc modifications. 54,55 Our evaluation of O-GlcNAc and OGT protein expression levels reveals a significant upregulation of both O-GlcNAc and OGT expression in the Δpmr1 mutant versus WT strain. Upon addition of Mn 2+ , the glycosylation levels in the WT strain remained stable, while those in the Δpmr1 mutant rebounded to normal levels (Figure 6G,H).…”

Section: Characterization Of Pmr1mentioning

confidence: 93%

The Development of Aspergillus flavus and Biosynthesis of Aflatoxin B1 are Regulated by the Golgi-Localized Mn²⁺ Transporter Pmr1

Qu,

Chi,

2024

J. Agric. Food Chem.

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Microorganisms rely on diverse ion transport and trace elements to sustain growth, development, and secondary metabolism. Manganese (Mn 2+ ) is essential for various biological processes and plays a crucial role in the metabolism of human cells, plants, and yeast. In Aspergillus flavus, we confirmed that Pmr1 localized in cis-and medial-Golgi compartments was critical in facilitating Mn 2+ transport, fungal growth, development, secondary metabolism, and glycosylation. In comparison to the wild type, the Δpmr1 mutant displayed heightened sensitivity to environmental stress, accompanied by inhibited synthesis of aflatoxin B1, kojic acid, and a substantial reduction in pathogenicity toward peanuts and maize. Interestingly, the addition of exogenous Mn 2+ effectively rectified the developmental and secondary metabolic defects in the Δpmr1 mutant. However, Mn 2+ supplement failed to restore the growth and development of the Δpmr1Δgdt1 double mutant, which indicated that the Gdt1 compensated for the functional deficiency of pmr1. In addition, our results showed that pmr1 knockout leads to an upregulation of O-glycosyl-Nacetylglucose (O-GlcNAc) and O-GlcNAc transferase (OGT), while Mn 2+ supplementation can restore the glycosylation in A. flavus. Collectively, this study indicates that the pmr1 regulates Mn 2+ via Golgi and maintains growth and metabolism functions of A. flavus through regulation of the glycosylation.

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“…The cytoplasmic branched-chain aminotransferase (BCAT1) and/or the mitochondrial branched-chain aminotransferase (BCAT2) isoenzymes transform BCAAs into corresponding branched-chain α-keto acids (BCKAs). This bioconversion consists in moving the α-amino group onto α-KG and producing glutamate, which in turn is a crucial metabolite for nucleotide and non-essential amino acids biosynthesis [ 147 , 148 ]. On the other hand, BCKAs are used as indirect sources of acetyl-CoA and succinyl-CoA that are then enrolled in the TCA cycle for ATP generation [ 147 , 149 , 150 ].…”

Section: A Comprehensive Picture Of Liver Cancer Cell Metabolismmentioning

confidence: 99%

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

Foglia

Beltrà

Sutti

et al. 2023

IJMS

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Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC’s metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

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Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression

Cited by 19 publications

References 40 publications

BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

The Development of Aspergillus flavus and Biosynthesis of Aflatoxin B1 are Regulated by the Golgi-Localized Mn²⁺ Transporter Pmr1

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

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Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression

Cited by 19 publications

References 40 publications

BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

The Development of Aspergillus flavus and Biosynthesis of Aflatoxin B1 are Regulated by the Golgi-Localized Mn2+ Transporter Pmr1

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

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The Development of Aspergillus flavus and Biosynthesis of Aflatoxin B1 are Regulated by the Golgi-Localized Mn²⁺ Transporter Pmr1