Dataset Information

SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma.

ABSTRACT: Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β (SUCLG2) can affect the overall succinylation of lung adenocarcinoma (LUAD) cells. Succinylome analysis shows that the deletion of SUCLG2 can upregulate the succinylation level of mitochondrial proteins and inhibits the function of key metabolic enzymes by reducing either enzymatic activity or protein stability, thus dampening mitochondrial function in LUAD cells. Interestingly, SUCLG2 itself is also succinylated on Lys93, and this succinylation enhances its protein stability, leading to the upregulation of SUCLG2 and promoting the proliferation and tumorigenesis of LUAD cells. Sirtuin 5 (SIRT5) desuccinylates SUCLG2 on Lys93, followed by tripartite motif-containing protein 21 (TRIM21)-mediated ubiquitination through K63-linkage and degradation in the lysosome. The findings reveal a new role for SUCLG2 in mitochondrial dysfunction and clarify the mechanism of the succinylation-mediated protein homeostasis of SUCLG2 in LUAD, thus providing a theoretical basis for developing anti-cancer drugs targeting SUCLG2.

SUBMITTER: Hu Q

PROVIDER: S-EPMC10724390 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma.

Hu Qifan Q Xu Jing J Wang Lei L Yuan Yi Y Luo Ruiguang R Gan Mingxi M Wang Keru K Zhao Tao T Wang Yawen Y Han Tianyu T Wang Jian-Bin JB

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231030 35

Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β (SUCLG2) can affect the overall succinylation of lung adenocarcinoma (LUAD) cells. Succinylome analysis shows that the deletion of SUCLG2 can upregulate the succinylation level of mit ...[more]

PMID: 37904651

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Project description:BackgroundRas guanine nucleotide-releasing protein 2 (RASGRP2), one of the guanine nucleotide exchange factors (GEFs), has attracted much attention in recent years. However, the correlation between RASGRP2 and immune infiltration and malignant features in lung adenocarcinoma (LUAD) has rarely been mentioned.MethodsThe Limma package and the LASSO regression model were performed to screen for differentially expressed genes. Data from the TCGA and 5 GEO databases were used to explore the expression level of RASGRP2 in LUAD patients. A weighted co-expression network and LinkFinder module were established to find the related genes of RASGRP2. The ESTIMATE algorithm was used to analyze the correlation between RASGRP2 and immune infiltration in LUAD. Tumor-infiltrating immune cells were sorted and sequenced at the single-cell level to analyze differences in RASGRP2. Real-time PCR and immunohistochemistry were performed in the real-world cohort to verify the expression of RASGRP2 and its correlation with immune-related genes. Clone formation and EdU assays were used to verify the proliferation ability. The proportion of apoptotic cells was analyzed by flow cytometry. Observation of mitochondrial membrane potential (MMP) changes by fluorescence microscopy.ResultsOur results suggested that decreased RASGRP2 was associated with worse clinical parameters and prognosis in LUAD patients. And we constructed a FLI1-HSA-miR-1976-RASGRP2 transcriptional network to support the role of RASGRP2. Enrichment analysis revealed that RASGRP2 was involved in lymphocyte activation and leukocyte adhesion. RASGRP2 was found to be positively correlated with the infiltration of most immune cells, immunoregulators, and chemokines in a subsequent study. Meanwhile, the real-world cohort confirmed that the expression levels of PDCD1, CTLA4, CD40LG, CCL14, CXCR5, and CCR7 were higher in the high-RASGRP2 expression group. Cytological experiments proved that RASGRP2 inhibited cell proliferation in LUAD by regulating mitochondrial-dependent apoptosis.ConclusionRASGRP2 was a potential immune-related biomarker of LUAD. In addition, RASGRP2 was involved in the malignant progression of LUAD through the regulation of mitochondrial-dependent apoptosis.

Dataset Information

SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma.

Publications

SUCLG2 Regulates Mitochondrial Dysfunction through Succinylation in Lung Adenocarcinoma.

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