The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?

Zhang, Lin; Kim, Sungjune; Ren, Xiubao

doi:10.3389/fonc.2020.01721

Cited by 48 publications

(43 citation statements)

References 80 publications

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“…Currently, the literature supports diverging functions for SIRT2 in tumorigenesis, in a context-dependent manner, that act to modify epigenetic pathways implicated in cancer’s initiation, promotion, and progression 44 – 46 . Our findings illustrate the novel capacity of SIRT2 to enhance subcutaneous melanoma progression while raising the vital question of at what point does SIRT2, a tumor suppressor protein that promotes genomic integrity in healthy cells, transition into what can only be described as a tumor promoter.…”

Section: Discussionmentioning

confidence: 99%

SIRT2 promotes murine melanoma progression through natural killer cell inhibition

Zhang

Acklin

Gillenwater

et al. 2021

Sci Rep

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SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.

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Section: Discussionmentioning

confidence: 99%

SIRT2 promotes murine melanoma progression through natural killer cell inhibition

Zhang

Acklin

Gillenwater

et al. 2021

Sci Rep

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“…It has been reported that G1 phase cell cycle arrest is associated with the inhibition of SIRT2 expression. 17 Fluorescence microscopy demonstrated that Gs-Rg3 decreased SIRT2 levels in a dose-dependent manner (Figure 4(A)), which was confirmed through Western blot analysis. Furthermore, Gs-Rg3mediated SIRT2 level reductions increased the global cellular acetylation of H3K18 and H4K16 (Figure 4(B) and (C)), indicating that Gs-Rg3 suppresses SIRT2 levels and promotes the acetylation of SIRT2 target sites, thereby regulating the HCC (Bel-7402 and HCCLM3) cell cycle and proliferation.…”

Section: Exposure To Gs-rg3 Decreases Sirt2 Levels Concomitant With Increased Histone Acetylationmentioning

confidence: 66%

In Vitro Validation of Network Pharmacology Predictions: Ginsenoside Rg3 Inhibits Hepatocellular Carcinoma Cell Proliferation via SIRT2

Zheng

Qiu

Sun

et al. 2021

Natural Product Communications

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To elucidate the molecular mechanisms underlying the therapeutic activity of ginsenoside Rg3 (Gs-Rg3) in the context of hepatocellular carcinoma (HCC). Methods Relevant databases were searched to identify protein targets that were both dysregulated and implicated in HCC, as well as targeted by Gs-Rg3. Generation of a protein-protein interaction network facilitated the selection of connected nodes for the construction of a shared disease- and drug-target interaction network model, and topological analysis identified the most highly connected nodes. Targets were annotated with their associated Gene Ontology terms, followed by Kyoto Encyclopedia of Genes and Genomes biological pathway enrichment analysis. In vitro experiments using 2 hours CC cell lines (Bel-7402 and HCCLM3) were performed to investigate the impact of Gs-Rg3 on cell proliferation, viability, cell cycle, cyclin D1 and sirtuin 2 (SIRT2) levels, and global cellular histone acetylation (specifically H3K18ac and H4K16ac). Results Network pharmacology suggested that Gs-Rg3 synergistically targets multiple proteins and pathways relevant to HCC pathogenesis, including those involved in cell cycle and proliferation. In vitro experiments confirmed that Gs-Rg3 dose-dependently inhibits cell proliferation and viability; induces G1 phase cell cycle arrest; decreases cyclin D1, cyclin-dependent kinase 2 (CDK2), and SIRT2 levels; and enhances global H3K18ac and H4K16ac. Conclusions Hypotheses derived from the network analysis were confirmed in vitro. Gs-Rg3 induces G1 phase cell cycle arrest, concomitant with decreased cyclin D1 and CDK2 levels, suggesting a possible mechanism for inhibiting proliferation. In addition, Gs-Rg3 decreases SIRT2 levels, concomitant with enhanced global H3K18ac and H4K16ac. These findings provide a theoretical basis and a support for further preclinical study of the safety and antineoplastic molecular mechanisms of Gs-Rg3, with the goal of eventual clinical translation.

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“…Currently, the literature supports diverging functions for SIRT2 in tumorigenesis, in a context-dependent manner, that act to modify epigenetic pathways implicated in cancer's initiation, promotion, and progression [38][39][40]. Our ndings illustrate the novel capacity of SIRT2 to enhance subcutaneous melanoma progression while raising the vital question of at what point does SIRT2, a protein that promotes genomic integrity in healthy cells, transition into what can only be described as a cancer promoter.…”

Section: Discussionmentioning

confidence: 77%

SIRT2 Promotes Murine Melanoma Progression Through Natural Killer Cell Inhibition

Zhang

Acklin

Gillenwater

et al. 2020

Preprint

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SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine xenograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell activation and proliferation within the tumor microenvironment (TME). Furthermore, despite the effect of increased tumor growth rate and tumor volume in wild-type littermate mice, NK cell depletion does not affect that in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses melanoma tumor growth in mice. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which promotes melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.

show abstract

The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?

Cited by 48 publications

References 80 publications

SIRT2 promotes murine melanoma progression through natural killer cell inhibition

SIRT2 promotes murine melanoma progression through natural killer cell inhibition

In Vitro Validation of Network Pharmacology Predictions: Ginsenoside Rg3 Inhibits Hepatocellular Carcinoma Cell Proliferation via SIRT2

SIRT2 Promotes Murine Melanoma Progression Through Natural Killer Cell Inhibition

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