SDHB Suppresses the Tumorigenesis and Development of ccRCC by Inhibiting Glycolysis

Fang, Zhiyu; Sun, Qiang; Yang, Huihui; Zheng, Junfang

doi:10.3389/fonc.2021.639408

Cited by 30 publications

(21 citation statements)

References 40 publications

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“…In addition, this study revealed that the expression of SDH genes is significantly correlated with the infiltration levels of B cells and CD4 + T cells in ccRCC. Therefore, SDH genes participate in the tumorigenesis of ccRCC and may serve as a potential prognostic biomarker in ccRCC, which is partly consistent with Fang’s study [ 52 ]. Notably, our findings suggest that all the four subunits are closely linked to ccRCC progression.…”

Section: Discussionsupporting

confidence: 87%

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

Yang

Zhou

et al. 2022

Bioengineered

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas, with high mortality and poor prognoses worldwide. Succinate dehydrogenase (SDH) consists of four nuclear-encoded subunits and it is the only complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Previous studies have shown decreased SDH activity in ccRCC. However, the role and underlying molecular mechanisms of SDH in ccRCC initiation and development remain unclear. In the present study, pan-cancer analysis of SDH gene expression was analyzed and the relationship between SDH gene expression and clinicopathological parameters was assessed using different databases. cBioPortal, UACLAN, and Tumor Immune Estimation Resource (TIMER) were subsequently utilized to analyze genetic alterations, methylation, and immune cell infiltration of SDH genes in ccRCC patients. We found SDHs were significantly downregulated in ccRCC tissues and correlated with ccRCC progression. Increased methylation and high SDH promoter mutation rates may be the cause of reduced expression of SDHs in ccRCC. Moreover, the interaction network showed that SDH genes were correlated with ferroptosis-related genes. We further demonstrated that SDH inhibition dampened oxidative phosphorylation, reduced ferroptotic events, and restored ferroptotic cell death, characterized by eliminated mitochondrial ROS levels, decreased cellular ROS and diminished peroxide accumulation. Collectively, this study provides new insights into the regulatory role of SDH in the carcinogenesis and progression of ccRCC, introducing a potential target for advanced antitumor therapy through ferroptosis.

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Section: Discussionsupporting

confidence: 87%

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

Yang

Zhou

et al. 2022

Bioengineered

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“…According to histopathological classification, RCC has three main subtypes: papillary renal cell carcinoma, clear cell renal cell carcinoma (ccRCC), and chromophobe cell renal carcinoma. Among them, ccRCC is the most frequent histological subtype, accounting for 80-90% [ 2 ]. Clinically, due to no evident symptoms at early stage and insufficient specific diagnostic markers, 20-30% of ccRCC patients have been in advanced-stage and developed metastasis when diagnosed [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

LINC00887 Fosters Development of Clear Cell Renal Cell Carcinoma via Inhibiting CD8+ T Cell Immune Infiltration

Lin

Zhang

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. lncRNAs affect adaptive and innate immunity of cancer via mediating functional states of immune cells, genes, and pathways. Nonetheless, little is known about the molecular mechanism of lncRNA-mediated CD8+ T cell immune infiltration in progression of clear cell renal cell carcinoma (ccRCC). We designed this work to investigate the role of LINC00887 in regulating CD8+ T cell immune infiltration in ccRCC. Methods. Correlation between LINC00887 and immune factors and the expression level of LINC00887 in ccRCC were analyzed by bioinformatics methods (TCGA-KIRC database, “edgeR” package, “clusterProfiler” package, and “CIBERSORT” package). LINC00887 expression in ccRCC was examined via RT-qPCR. The cytokilling capacity of CD8+ T cells was evaluated by the lactate dehydrogenase assay. The apoptotic ability of CD8+ T cells was measured by flow cytometry. The chemotactic ability of CD8+ T cells was revealed by chemotaxis assay. CXCR3, CXCL9, and CXCL10 levels were assessed by RT-qPCR. Results. As suggested by bioinformatics analysis, LINC00887 was markedly upregulated in ccRCC patients and associated with expression of immune-suppression molecule, thereby abating the immune infiltration level of CD8+ cells in tumor tissue. As revealed by cellular assay, LINC00887 was upregulated in ccRCC cells, and knockdown of LINC00887 resulted in a decreased PD-L1 expression, increased CD8+ T cell toxicity, decreased apoptotic levels, and enhanced chemotaxis. Moreover, we found that LINC00887 exhibited inhibitory effect on immune infiltration of CD8+ cells in clinical tissues. Conclusions. The results of this study suggested that LINC00887 promoted ccRCC progression by inhibiting immune infiltration of CD8+ T cells, providing new insights into pathogenesis of ccRCC and suggesting LINC00887 being a promising immunotherapy target for ccRCC.

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“…IHC was performed as described before ( 15 ). The sections were incubated with anti‐GLUD1 antibody (Cat# PTM-5632, 1:100, PTM Biolabs Inc., Hangzhou, China).…”

Section: Methodsmentioning

confidence: 99%

GLUD1 suppresses renal tumorigenesis and development via inhibiting PI3K/Akt/mTOR pathway

Wang

Fang²,

Gao³

et al. 2022

Front. Oncol.

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Growing cancer cells are addicted to glutamine. Glutamate dehydrogenase 1 (GLUD1) is one of key enzymes in glutamine metabolism and plays a critical role in the malignancy of diverse tumors. However, its role and molecular mechanism in clear cell renal cell carcinoma (ccRCC) development and progression remain unknown. In this study, analysis results of the GEO/TCGA/UALCAN database showed that GLUD1 level was downregulated in ccRCC tissues. Immunohistochemistry and western blotting results further validated the downregulation of GLUD1 level in ccRCC tissues. GLUD1 level was gradually decreased as ccRCC stage and grade progressed. Low GLUD1 level was associated with a shorter survival and higher IC50 value for tyrosine kinase inhibitors (TKIs) in ccRCC, reminding that GLUD1 level could predict the prognosis and TKIs sensitivity of ccRCC patients. High level of methylation in GLUD1 promoter was positively correlated with the downregulation of GLUD1 level and was negatively correlated with survival of ccRCC patients. GLUD1 overexpression suppressed RCC cell proliferation, colony formation and migration by inhibiting PI3K/Akt/mTOR pathway activation. Low GLUD1 level correlated with suppressive immune microenvironment (TIME) in ccRCC. Together, we found a novel tumor-suppressing role of GLUD1 in ccRCC which was different from that in other tumors and a new mechanism for inhibiting PI3K/Akt/mTOR activation and TIME in ccRCC. These results provide a theoretical basis for GLUD1 as a therapeutic target and prognostic marker in ccRCC.

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SDHB Suppresses the Tumorigenesis and Development of ccRCC by Inhibiting Glycolysis

Cited by 30 publications

References 40 publications

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

Functional deficiency of succinate dehydrogenase promotes tumorigenesis and development of clear cell renal cell carcinoma through weakening of ferroptosis

LINC00887 Fosters Development of Clear Cell Renal Cell Carcinoma via Inhibiting CD8+ T Cell Immune Infiltration

GLUD1 suppresses renal tumorigenesis and development via inhibiting PI3K/Akt/mTOR pathway

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