Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.
J Virol. 2019 Jul 17;93(15). doi: 10.1128/JVI.00626-19. Print 2019 Aug 1.
Oncolytic virotherapy represents a promising experimental anticancer strategy, based on the use of genetically modified viruses to selectively infect and kill cancer cells. Vesicular stomatitis virus (VSV) is a prototypic oncolytic virus (OV) that induces cancer cell death through activation of the apoptotic pathway, although intrinsic resistance to oncolysis is found in some cell lines and many primary tumors, as a consequence of residual innate immunity to the virus. In the effort to improve OV therapeutic efficacy, we previously demonstrated that different agents, including histone deacetylase inhibitors (HDIs), functioned as reversible chemical switches to dampen the innate antiviral response and improve the susceptibility of resistant cancer cells to VSV infection. In the present study, we demonstrated that the NAD-dependent histone deacetylase SIRT1 (silent mating type information regulation 2 homolog 1) plays a key role in the permissivity of prostate cancer PC-3 cells to VSVΔM51 replication and oncolysis. HDI-mediated enhancement of VSVΔM51 infection and cancer cell killing directly correlated with a decrease of SIRT1 expression. Furthermore, pharmacological inhibition as well as silencing of SIRT1 by small interfering RNA (siRNA) was sufficient to sensitize PC-3 cells to VSVΔM51 infection, resulting in augmentation of virus replication and spread. Mechanistically, HDIs such as suberoylanilide hydroxamic acid (SAHA; Vorinostat) and resminostat upregulated the microRNA miR-34a that regulated the level of SIRT1. Taken together, our findings identify SIRT1 as a viral restriction factor that limits VSVΔM51 infection and oncolysis in prostate cancer cells. The use of nonpathogenic viruses to target and kill cancer cells is a promising strategy in cancer therapy. However, many types of human cancer are resistant to the oncolytic (cancer-killing) effects of virotherapy. In this study, we identify a host cellular protein, SIRT1, that contributes to the sensitivity of prostate cancer cells to infection by a prototypical oncolytic virus. Knockout of SIRT1 activity increases the sensitivity of prostate cancer cells to virus-mediated killing. At the molecular level, SIRT1 is controlled by a small microRNA termed miR-34a. Altogether, SIRT1 and/or miR-34a levels may serve as predictors of response to oncolytic-virus therapy.
溶瘤病毒治疗代表了一种很有前途的实验性抗癌策略，其基于使用基因改造病毒来选择性地感染和杀死癌细胞。水疱性口炎病毒（VSV）是一种典型的溶瘤病毒（OV），它通过激活凋亡途径诱导癌细胞死亡，尽管一些细胞系和许多原发性肿瘤存在内在的抗溶瘤作用，这是由于对病毒的残留固有免疫。为了提高 OV 的治疗效果，我们之前的研究表明，不同的药物，包括组蛋白去乙酰化酶抑制剂（HDIs），作为可逆的化学开关起作用，以抑制先天抗病毒反应，并提高耐药癌细胞对 VSV 感染的敏感性。在本研究中，我们证明 NAD 依赖性组蛋白去乙酰化酶 SIRT1（沉默交配型信息调节 2 同源物 1）在前列腺癌细胞 PC-3 对 VSVΔM51 复制和溶瘤作用的易感性中起关键作用。HDIs 介导的 VSVΔM51 感染和癌细胞杀伤的增强与 SIRT1 表达的降低直接相关。此外，通过药理学抑制以及通过小干扰 RNA（siRNA）沉默 SIRT1，足以使 PC-3 细胞对 VSVΔM51 感染敏感，从而增强病毒复制和扩散。从机制上讲，HDIs，如琥珀酰亚胺基羟肟酸（SAHA；伏立诺他）和 resminostat，上调了调节 SIRT1 水平的 microRNA miR-34a。总之，我们的研究结果表明 SIRT1 是一种病毒限制因子，它限制了前列腺癌细胞中 VSVΔM51 的感染和溶瘤作用。使用非致病性病毒来靶向和杀死癌细胞是癌症治疗的一种很有前途的策略。然而，许多类型的人类癌症对病毒治疗的溶瘤（杀伤癌症）作用具有抗性。在这项研究中，我们确定了一种宿主细胞蛋白 SIRT1，它有助于前列腺癌细胞对典型溶瘤病毒的感染敏感性。SIRT1 活性的敲除增加了前列腺癌细胞对病毒介导的杀伤的敏感性。在分子水平上，SIRT1 受一种称为 miR-34a 的小 microRNA 控制。总之，SIRT1 和/或 miR-34a 的水平可以作为对溶瘤病毒治疗反应的预测因子。
