Differential expression of the sirtuin family in renal cell carcinoma: Aspects of carcinogenesis and prognostic significance

Jeh, Seong Uk; Park, Jung Je; Lee, Jong Sil; Kim, Dong Chul; Do, Jungmo; Lee, Sin Woo; Choi, See Min; Hyun, Jae Seog; Seo, Deok Ha; Lee, Chunwoo; Kam, Sung Chul; Kihan, Chung; Hwa, Jeong Seok

doi:10.1016/j.urolonc.2017.08.016

Cited by 32 publications

(28 citation statements)

References 31 publications

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“…In primary RCC, SIRT1 expression was decreased compared with normal kidney tissues, particularly for ccRCC. Our results are in accordance with the only report available thus far [54]. Thus, our results further support a tumor-suppressive role of SIRT1 in RCC.…”

Section: Discussionsupporting

confidence: 93%

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Miranda‐Gonçalves

Lameirinhas

Macedo-Silva

et al. 2020

Cells

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Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms' regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate's impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.

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Section: Discussionsupporting

confidence: 93%

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Miranda‐Gonçalves

Lameirinhas

Macedo-Silva

et al. 2020

Cells

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“…SIRT1 act as a direct target of miRNA-200a and miRNA-22, miRNA-200a and miR-22 could inhibit cell proliferation, arrested cell cycle progression, and promoted cell apoptosis in RCC cell lines (11,27). However, it was also reported that SIRT1 expression was significantly lower in RCC than in normal tissues and high expression of SIRT1 was correlated with a better prognosis for RCC patients (8). SIRT1 overexpression inhibited RCC cell line proliferation by repressing FGB expression (9).…”

Section: Discussionmentioning

confidence: 99%

“…SIRT3 was deleted or down-regulated in many types of human cancers (31). In renal cancer, SIRT3 was reported to be down-regulated in KIRC tissues and predicted a favorable survival of KIRC patients (8,13,32). Overexpression of SIRT3 in RCC cell lines inhibited cell proliferation and reversed the Warburg effect (13).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have been conducted to explore the clinical significance of sirtuins in RCC, however, the results are inconsistent. The protein expression of SIRT1, SIRT3, and SIRT6 have been reported to be significantly lower in human RCC tissues compared with that in adjacent normal tissues, and high protein expression levels of SIRT1 and SIRT3 were found to be significantly associated with better survival in RCC patients (8,9). However, SIRT1 was also reported to be up-regulated in RCC and the expression of SIRT1 was significantly associated with poor prognosis in RCC patients (10).…”

Section: Introductionmentioning

confidence: 99%

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Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

Tan

Peng

et al. 2020

Front. Oncol.

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Sirtuins, class III histone deacetylases, are involved in multiple biological processes in cancer initiation and progression. However, the diverse expression patterns and prognostic values of sirtuins in cancers have yet to be elucidated. In this study, we first evaluated the expression and prognostic values of sirtuins in multiple cancer cohorts using publicly available TCGA pan-cancer datasets. Pan-cancer survival analysis indicated that 6 out of 7 sirtuin family members were significant associated with prognosis of clear cell renal cell carcinoma (KIRC) patients. SIRT1, SIRT3, SIRT4, and SIRT5 were associated with favorable prognosis of KIRC patients, while SIRT6 and SIRT7 were associated with unfavorable prognosis. The expression levels of SIRT4 and SIRT5 in KIRC tissues were lower than that in normal tissues, while SIRT6 and SIRT7 were higher in KIRC tissues. The expression levels of SIRT1, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly correlated with tumor stage and histological grade. DNA methylation may contribute to the dysregulation of sirtuins. Finally, GSEA was conducted to predict the potential functions of sirtuins in KIRC. Our results may provide novel insights for the development of sirtuins-based cancer therapy in KIRC.

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“…Zhang et al 22 collected 248 primary HCC specimens and found the patients with high SIRT3 expression tended to have longer overall survival (OS) compared to patients with low SIRT3 expression (hazard ratio [HR]=0.56, 95% CI=0.34–0.90, P =0.016). Similarly, Jeh et al 26 validated that renal cell carcinoma (RCC) patients with high SIRT3 expression had longer OS (HR=0.13, 95% CI=0.02–0.94, P =0.047). However, different observations were made in other studies.…”

Section: Introductionmentioning

confidence: 87%

Prognostic and clinicopathological value of SIRT3 expression in various cancers: a systematic review and meta-analysis

Zhou¹,

Cheng²,

Chen³

et al. 2018

OTT

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BackgroundSeveral studies have explored the prognostic value of sirtuin 3 (SIRT3) in various cancers, but obtained inconsistent results. The current systematic review and meta-analysis was conducted to investigate the association between SIRT3 expression and prognosis in various cancers.MethodsPubMed, Embase, Web of Science and the Cochrane Library were comprehensively retrieved by the end of September 29, 2017. All the relevant studies were checked and included in the meta-analysis if they met the inclusion criteria.ResultsA total of 17 studies involving 2,865 patients were included in the systematic review and meta-analysis. The results indicated that SIRT3 expression was not significantly associated with overall survival (OS) (hazard ratio [HR]=0.87, 95% CI=0.59–1.29, P=0.50) and disease-free survival (HR=0.87, 95% CI=0.57–1.31, P=0.50) in total various cancers. However, significant relationship between SIRT3 expression and OS in specific cancers was detected, including chronic lymphocytic leukemia (CLL) (HR=0.48, 95% CI=0.26–0.89, P=0.019), hepatocellular carcinoma (HCC) (HR=0.56, 95% CI=0.42–0.74, P<0.001), pancreatic carcinoma (PC) (HR=0.55, 95% CI=0.30–1.00, P=0.049), renal cell carcinoma (RCC) (HR=0.13, 95% CI=0.02–0.98, P=0.048), breast cancer (BC) (HR=2.53, 95% CI=1.83–3.67, P<0.001), colon cancer (CC) (HR=1.87, 95% CI=1.12–3.26, P=0.022) and non-small-cell lung cancer (NSCLC) (HR=2.20, 95% CI=1.38–3.50, P=0.001). Moreover, SIRT3 expression was obviously associated with tumor size (odds ratio [OR]=1.41, 95% CI=1.02–1.94, P=0.04), tumor differentiation (OR=1.52, 95% CI=1.08–2.16, P=0.02) and clinical stage (OR=2.07, 95% CI=1.23–3.46, P=0.01) in HCC.ConclusionSIRT3 was distinctly related to the OS in specific cancers. SIRT3 was an unfavorable prognostic factor in BC, CC and NSCLC; however, it was also a favorable prognostic factor in CLL, HCC, PC and RCC, especially in HCC.

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Differential expression of the sirtuin family in renal cell carcinoma: Aspects of carcinogenesis and prognostic significance

Cited by 32 publications

References 31 publications

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

Prognostic and clinicopathological value of SIRT3 expression in various cancers: a systematic review and meta-analysis

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