Abstract
BackgroundThe aim of this study was to investigate the biological functions and underlying mechanisms of SIRT5 in clear cell renal cell carcinoma (ccRCC).MethodsSIRT5 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.ResultsSIRT5 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.ConclusionsDownregulated 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.
Highlights
The aim of this study was to investigate the biological functions and underlying mechanisms of SIRT5 in clear cell renal cell carcinoma
SIRT5 is downregulated and associated with a poor prognosis for patients with ccRCCThe RNA-seq datasets and clinical information of patients with clear cell renal cell carcinoma (ccRCC) were downloaded from The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/)
We further detected the expression of SIRT5 in 72 paired ccRCC tumor samples obtained from Ruijin Hospital and found that SIRT5 expression was significantly decreased in the tumor samples compared with paracancerous normal tissues (P = 4.117e−09) (Fig. 1B)
Summary
The aim of this study was to investigate the biological functions and underlying mechanisms of SIRT5 in clear cell renal cell carcinoma (ccRCC). Clear cell renal cell carcinoma (ccRCC), accounting for > 80% of the histopathological types of sporadic RCC, is associated with worse survival outcomes than other subtypes [2]. Metastatic ccRCC has a poor prognosis, and the 5-year overall survival (OS) rate is approximately 10%, while the 5-year OS rate of surgically treated stage I ccRCC is > 90% [3]. Combination strategies, including surgery, targeted therapy, and immunotherapy, have optimized the overall efficacy of ccRCC treatment, the clinical efficiency is still limited, especially in. Investigations of the detailed molecular mechanisms underlying the tumorigenesis of ccRCC and novel therapeutic strategies are urgently needed
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