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SIRT5 functions as a tumor suppressor in renal cell carcinoma by reversing the Warburg effect
Liu Yihan1, Wang Xiaojing2, Liu Ao2
1Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, 06520, USA.
Background:
The aim of this study was to investigate the biological functions and underlying mechanisms of SIRT5 in clear cell renal cell carcinoma (ccRCC).
Methods:
SIRT5 expression data in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) were selected, and the correlations between SIRT5 expression and various clinicopathological parameters were analysed. SIRT5 expression in ccRCC tissues was examined using immunohistochemistry. Stable cell lines with SIRT5 knockdown were established. In vitro and in vivo experiments were conducted to investigate the functional roles of SIRT5 in the cellular biology of ccRCC, including cell viability assays, wound healing assays, soft agar colony formation assays, Transwell invasion assays, qRT-PCR, and Western blotting. In addition, microarrays, rescue experiments and Western blotting were used to investigate the molecular mechanisms underlying SIRT5 functions.
Results:
SIRT5 expression was downregulated in ccRCC compared with normal tissues, which correlated with a poor prognosis of ccRCC. SIRT5 knockdown significantly increased cell proliferation, migration and invasion in vitro. In vivo experiments revealed that SIRT5 knockdown promoted ccRCC tumorigenesis and metastasis. Mechanistically, SIRT5 deglycosylated PDHA1 at K351 and increased PDC activity, thereby altering the metabolic crosstalk with the TCA cycle and inhibiting the Warburg effect. SIRT5 overexpression was related to low succinylation of PDHA1.
Conclusions:
Downregulated SIRT5 expression in ccRCC accelerated the Warburg effect through PDHA1 hypersuccinylation and induced tumorigenesis and progression, indicating that SIRT5 may become a potential target for ccRCC therapy.
Insights
Sirtuin 5 (SIRT5) is downregulated in clear cell renal cell carcinoma (ccRCC), promoting tumor growth and metastasis by affecting cellular metabolism. Restoring SIRT5 may offer a therapeutic strategy for ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Clear cell renal cell carcinoma (ccRCC) is a significant health concern.
- The role of Sirtuin 5 (SIRT5) in ccRCC pathogenesis requires elucidation.
Purpose of the Study:
- To investigate the biological functions and molecular mechanisms of SIRT5 in ccRCC.
- To assess SIRT5 as a potential therapeutic target for ccRCC.
Main Methods:
- Analysis of SIRT5 expression in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) dataset.
- Immunohistochemistry, cell line manipulation (SIRT5 knockdown), in vitro/in vivo assays, qRT-PCR, Western blotting, and microarrays were employed.
- Investigated SIRT5's impact on cell proliferation, migration, invasion, and tumorigenesis.
Main Results:
- SIRT5 expression was significantly downregulated in ccRCC tissues and correlated with poor prognosis.
- SIRT5 knockdown enhanced ccRCC cell proliferation, migration, and invasion in vitro and promoted tumor growth and metastasis in vivo.
- SIRT5 was found to deglycosylate PDHA1, increasing pyruvate dehydrogenase complex (PDC) activity, inhibiting the Warburg effect, and reducing PDHA1 succinylation.
Conclusions:
- Downregulated SIRT5 accelerates the Warburg effect via PDHA1 hypersuccinylation, driving ccRCC tumorigenesis and progression.
- SIRT5 represents a potential therapeutic target for ccRCC treatment.
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