SIRT5 Functions as a Tumor Suppressor via Reversing Warburg Effect in Renal Cell Carcinoma

Abstract Background: The aim of this study is to investigate the biological functions and the underlying mechanisms of SIRT5 in clear cell renal cell carcinoma (ccRCC).Methods: The datasets of SIRT5 expression in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) was selected and the correlation between SIRT5 and various clinicopathological parameters was analyzed. The SIRT5 expression in RCC tissues was examined by immunohistochemistry. The SIRT5 knockdown cell lines were constructed. In vitro and in vivo experiments were carried out to investigate the function of SIRT5 on cellular biology of RCC, including cell viability assay, wound-healing assay, soft agar colony formation assay, Transwell invasion assay, qRT-PCR, Western blot, etc. Besides, microarray, rescue experiment and Western blot were used to investigate the molecular mechanisms underlying the functions of SIRT5.Results: SIRT5 expression was downregulated in RCC tissues, and low expression of SIRT5 was correlated with poor prognosis of RCC. Knockdown of SIRT5 significantly prompted cell proliferation, migration, and facilitated invasion in vitro. In vivo experiments revealed that knocking down SIRT5 prompted ccRCC tumorigenesis and metastasis. SIRT5 deglycosylated PDHA1 at K351 and increased the activity of PDC, thus changing the metabolic pathway to the TCA cycle and inhibiting the Warburg effect. The overexpression of SIRT5 was related to the low succinylation of PDHA1.Conclusion: SIRT5 correlated with PDHA1 hyposuccinylation and progression in ccRCC, which suggested that SIRT5 might become a potential target for ccRCC therapy.