SIRT5 functions as a tumor suppressor in renal cell carcinoma by reversing the Warburg effect

Abstract

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.

Comprehensive analyses of PDHA1 that serves as a predictive biomarker for immunotherapy response in cancer

“…Previous research has demonstrated that decreased SIRT5 expression in KIRC accelerated the Warburg effect through PDHA1 hypersuccinylation, resulting in tumorigenesis and progression ( Yihan et al, 2021 ). Here, in KIRC, we found a negative correlation between the expression of PDHA1 and clinical staging by exploring TCGA-KIRC datasets.…”

Prognostic value of sirtuin family members and experimental verification identify SIRT5 as diagnostic biomarkers in clear cell renal cell carcinoma

“…Moreover, studies suggest that the expression of SIRT5 is decreased in ccRCC and that it can induce tumorigenesis and progression by accelerating the Warburg effect through PDHA1 hyper-succinylation. This indicates that SIRT5 might be a possible ccRCC suppressor ( Yihan et al, 2021 ). Other members in this family were also proven to be important for the tumorigenesis of many cancers.…”

“…One study showed that SIRT5 was found to suppress the development of HCC ( Sun et al, 2022 ). In ccRCC, SIRT family members are thought to regulate tumorigenesis, for example, SIRT5 downregulation was thought to promote metabolic reprogramming of ccRCC, the expression of SIRT5 was found to be decreased, and its downregulation can induce tumorigenesis and progression by accelerating the Warburg effect through PDHA1 hyper-succinylation, indicating that this marker might be a possible ccRCC suppressor ( Yihan et al, 2021 ). Although some SIRT members were proven to be important for the development and progression of ccRCC, for example, Tan et al.…”

Multiomic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma

“…Predicted targets of miR-10b among the GPR genes included Fanconi Anemia Complement Group C (FANCC), Kruppel Like Factor 11 (KLF11), SEC14 Like Lipid Binding 2 (SEC14L2), Sirtuin 5 (SIRT5), Sad1 and UNC84 Domain Containing 2 (SUN2), and Tripartite Motif Containing 35 (TRIM35), all of which have been implicated previously in the control of cell proliferation (25,28,31,(45)(46)(47)(48). We measured the expression level of these genes by qPCR after LNA-mediated miR-10b inhibition and observed small but significant changes in KLF11, SIRT5, and SEC14L2; a modest and significant upregulation of FANCC and SUN2; and a robust and significant increase in expression of TRIM35 (~2-fold) (Figure 8D).…”