BCKDK regulates the TCA cycle through PDC in the absence of PDK family during embryonic development

Heinemann-Yerushalmi, Lia; Bentovim, Lital; Felsenthal, Neta; Vinestock, Ron Carmel; Michaeli, Nofar; Krief, Sharon; Silberman, Alon; Cohen, Marina; Ben‐Dor, Shifra; Brenner, Ori; Haffner-Krausz, Rebecca; Itkin, Maxim; Malitsky, Sergey; Erez, Ayelet; Zelzer, Elazar

doi:10.1016/j.devcel.2021.03.007

Cited by 15 publications

(9 citation statements)

References 72 publications

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“…Recent studies have reported that BCKDK can inactivate the phosphorylation of pyruvate dehydrogenase complex to prevent pyruvate from entering the TCA cycle (48). The above research can partly explain why BCKDK knockout inhibited the glycolysis of A549 and H1299 in our study.…”

Section: Discussionsupporting

confidence: 64%

BCKDK alters the metabolism of non-small cell lung cancer

Wang¹,

Xiao²,

Jiang³

et al. 2021

Transl Lung Cancer Res

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Background: Metabolic reprogramming is a major feature of many tumors including non-small cell lung cancer (NSCLC). Branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in diabetes, obesity, and other diseases. However, the function of BCKDK in NSCLC is unclear. This study aimed to explore the function of BCKDK in NSCLC.Methods: Metabolites in the serum of patients with NSCLC and the supernatant of NSCLC cell cultures were detected using nuclear magnetic resonance (NMR) spectroscopy. Colony formation, cell proliferation, and cell apoptosis were assessed to investigate the function of BCKDK in the progression of NSCLC.Glucose uptake, lactate production, cellular oxygen consumption rate, extracellular acidification rate, and reactive oxygen species (ROS) were measured to examine the function of BCKDK in glucose metabolism.The expression of BCKDK was measured using reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemical assay.Results: Compared with healthy controls and postoperative NSCLC patients, increased branched-chain amino acid (BCAA) and decreased citrate were identified in the serum of preoperative NSCLC patients.Upregulation of BCKDK affected the metabolism of BCAAs and citrate in NSCLC cells. Knockout of BCKDK decreased the proliferation and exacerbated apoptosis of NSCLC cells ex vivo, while increased oxidative phosphorylation and, ROS levels, and inhibited glycolysis.Conclusions: BCKDK may influence glycolysis and oxidative phosphorylation by regulating the degradation of BCAA and citrate, thereby affecting the progression of NSCLC.

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Section: Discussionsupporting

confidence: 64%

BCKDK alters the metabolism of non-small cell lung cancer

Wang¹,

Xiao²,

Jiang³

et al. 2021

Transl Lung Cancer Res

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“…PDK is the enzyme responsible for phosphorylating pyruvate dehydrogenase and the metabolic switch from mitochondrial respiration to cytoplasmic glycolysis (Heinemann-Yerushalmi et al, 2021;Querfurth et al, 2022). PDK4 is decreased in a Frontiers in Genetics frontiersin.org variety of cancers, such as gastric cancer, prostate cancer, breast cancer, lung cancer and liver cancer, and may be associated with the inhibition of cell proliferation and induction of apoptosis (Liu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

A novel anoikis-related prognostic signature associated with prognosis and immune infiltration landscape in clear cell renal cell carcinoma

Chen

Liu²,

Zhu³

et al. 2022

Front. Genet.

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Background: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). Anoikis plays an essential function in tumourigenesis, whereas the role of anoikis in ccRCC remains unclear.Methods: Anoikis-related genes (ARGs) were collected from the MSigDB database. According to univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized to select the ARGs associated with the overall rate (OS). Multivariate Cox regression analysis was conducted to identify 5 prognostic ARGs, and a risk model was established. The Kaplan-Meier survival analysis was used to evaluate the OS rate of ccRCC patients. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Gene set enrichment analysis (GSVA) were utilized to investigate the molecular mechanism of patients in the low- and high-risk group. ESTIMATE, CIBERSOT, and single sample gene set enrichment analysis (ssGSEA) algorithms were conducted to estimate the immune infiltration landscape. Consensus clustering analysis was performed to divide the patients into different subgroups.Results: A fresh risk model was constructed based on the 5 prognostic ARGs (CHEK2, PDK4, ZNF304, SNAI2, SRC). The Kaplan-Meier survival analysis indicated that the OS rate of patients with a low-risk score was significantly higher than those with a high-risk score. Consensus clustering analysis successfully clustered the patients into two subgroups, with a remarkable difference in immune infiltration landscape and prognosis. The ESTIMATE, CIBERSORT, and ssGSEA results illustrated a significant gap in immune infiltration landscape of patients in the low- and high-risk group. Enrichment analysis and GSVA revealed that immune-related signaling pathways might mediate the role of ARGs in ccRCC. The nomogram results illustrated that the ARGs prognostic signature was an independent prognostic predictor that distinguished it from other clinical characteristics. TIDE score showed a promising immunotherapy response of ccRCC patients in different risk subgroups and cluster subgroups.Conclusion: Our study revealed that ARGs play a carcinogenic role in ccRCC. Additionally, we firstly integrated multiple ARGs to establish a risk-predictive model. This study highlights that ARGs could be implemented as a stratification factor for individualized and precise treatment in ccRCC patients.

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“…Interestingly enough, the increased acetylation level of PGK1 at K323 may promote its enzyme activity and exacerbate the EMT process in ovarian cancer cells ( Hu et al, 2017 ; Gou et al, 2021 ). Furthermore, as one of the downstream enzymes of HIF-1α, PDK-1 (HG/NG: 0.688AT Kac212) is known to be associated with apoptosis and the TCA cycle ( Saurus et al, 2015 ; Heinemann-Yerushalmi et al, 2021 ). In brief, these findings does not rule out of the possibility that lysine acetylation may play a regulatory role in the HIF-1 α pathway and may also affect apoptosis and EMT.…”

Section: Discussionmentioning

confidence: 99%

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

Wan

Jiang

et al. 2021

Front. Genet.

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Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.

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BCKDK regulates the TCA cycle through PDC in the absence of PDK family during embryonic development

Cited by 15 publications

References 72 publications

BCKDK alters the metabolism of non-small cell lung cancer

BCKDK alters the metabolism of non-small cell lung cancer

A novel anoikis-related prognostic signature associated with prognosis and immune infiltration landscape in clear cell renal cell carcinoma

Lysine Acetylation in the Proteome of Renal Tubular Epithelial Cells in Diabetic Nephropathy

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