The sirtuins (SIRTs), including seven family members, belong to class III histone deacetylase (HDAC) enzymes, which have been intensively investigated in cancers. Although the function of SIRTs in the cancer immunology is explored, SIRT-specific mechanisms regulating necroptosis-related innate immune response are not clear. In our present study, we found that both the mRNA and protein expression levels of SIRT3 and SIRT6 are significantly increased in the PCa tissues (HR, CI ; HR, CI ; and HR, CI ) and were associated with patients’ Gleason score and nodal metastasis. Furthermore, multivariate analysis showed that the PCa patients with higher expression levels of SIRT3 and SIRT6 had shorter overall survival (OS). Mechanistically, we found that SIRT3 and SIRT6 promote prostate cancer progress by inhibiting RIPK3-mediated necroptosis and innate immune response. Knockdown of both SIRT3 and SIRT6 not only activates TNF-induced necroptosis but also refreshes the corresponding recruitment of macrophages and neutrophils. Overall, our study identified that SIRT3 and SIRT6 are key regulators of necroptosis during prostate cancer progression.

中文翻译：

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SIRT3 和 SIRT6 通过抑制坏死性凋亡介导的先天免疫反应促进前列腺癌进展

Sirtuins (SIRT) 包括七个家族成员，属于 III 类组蛋白去乙酰化酶 (HDAC)，已在癌症中进行了深入研究。尽管探索了 SIRT 在癌症免疫学中的功能，但调节坏死性凋亡相关先天免疫反应的 SIRT 特异性机制尚不清楚。在我们目前的研究中，我们发现 SIRT3 和 SIRT6 的 mRNA 和蛋白质表达水平在 PCa 组织中显着增加（HR、CI; 人力资源、CI; 和人力资源，CI)并与患者的 Gleason 评分和淋巴结转移相关。此外，多变量分析表明，SIRT3 和 SIRT6 表达水平较高的 PCa 患者的总生存期 (OS) 较短。从机制上讲，我们发现 SIRT3 和 SIRT6 通过抑制 RIPK3 介导的坏死性凋亡和先天免疫反应来促进前列腺癌的进展。抑制 SIRT3 和 SIRT6 不仅会激活 TNF 诱导的坏死性凋亡，还会刷新巨噬细胞和中性粒细胞的相应募集。总体而言，我们的研究确定 SIRT3 和 SIRT6 是前列腺癌进展过程中坏死性凋亡的关键调节因子。