SIRT2 promotes murine melanoma progression through natural killer cell inhibition

Abstract

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.

Comprehensive Computational Analysis of Honokiol Targets for Cell Cycle Inhibition and Immunotherapy in Metastatic Breast Cancer Stem Cells

“…ese results confirm those of previous studies, in which SIRT2 expression level and CD8+ T cell infiltration level were positively correlated in breast cancer patients [51]. In addition, systemic SIRT2 has been suggested to promote tumor development by suppressing NK cells [42]. Interestingly, SIRT2 expression was significantly lower in breast cancer than in normal breast tissue, suggesting that SIRT2 may act as a tumor suppressor during the initiation of tumorigenesis.…”

“…In addition, it can greatly impact the e ectiveness of immunotherapy, highlighting the need of its further understanding [42].…”

“…In this study, we revealed that CCND1 expression was positively correlated with BRCA purity and macrophage in ltration levels, and negatively correlated with B cell and dendritic cell in ltration levels. Many studies have shown that tumor-associated macrophages play an important role in the proliferation, invasion, angiogenesis, and metastasis of human breast carcinoma, and that increased macrophage tumor in ltration confers metastatic potential and is associated with poor prognosis in breast cancer [42]. Our ndings are in line with those of Pestell et al, who demonstrated that cyclin D1 expression was increased in human cancer stroma, and promoted tumor in ammation, angiogenesis, and stem cell expansion in advanced breast cancer [41].…”

Epigenetics Regulates Antitumor Immunity in Melanoma

“…Systemic overexpression of SIRT2 promotes melanoma progression in immune-competent mice by suppressing the infiltration and function of NK cells in TME. Pharmacological inhibition of SIRT2 potentiates NK cell-dependent antitumor immunity and the growth of allograft melanoma ( 86 ), which might be of translational implication in increasing the efficacy of immunotherapy. Moreover, EZH2-mediated histone H3 methylation of HIF1α in macrophages leads to the silence of HIF1α expression and reprograms the immune suppressive microenvironment to the facilitative one, which alleviates the tumor burden and prolongs the overall survival of mice implanted with tumor ( 88 ).…”

Role of sirtuins in esophageal cancer: Current status and future prospects

“…There have been no reports on the role of sirtuins in immunotherapy of esophageal cancer, although some reports have appeared in other cancer types. Zhang et al [ 115 ] showed that pharmacological inhibition of SIRT2 increased natural killer cell infiltration into the tumor and suppressed tumor growth in allograft melanoma. Furthermore, Xiang et al [ 116 ] demonstrated that SIRT7 suppressed myocyte enhancer factor 2D acetylation and programmed death ligand 1 expression and promoted HCC cell proliferation.…”