Sirt6 通过介导 PI3K/Akt 信号通路促进弥漫大 B 细胞淋巴瘤的肿瘤发生和耐药性。
Sirt6 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling.
机构信息
Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University, No.324 Jingwu Road, Jinan, 250021, Shandong, China.
School of Medicine, Shandong University, Jinan, 250012, Shandong, China.
出版信息
J Exp Clin Cancer Res. 2020 Jul 25;39(1):142. doi: 10.1186/s13046-020-01623-w.
BACKGROUND
Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6.
METHODS
Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 were performed RNA-sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID beige mice to establish xenograft models.
RESULTS
Sirt6 is found to be overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level.
CONCLUSIONS
These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.
背景
Sirtuin 6（Sirt6）是一种高度保守的 ADP-ribosylase 和 NAD+依赖的去乙酰化酶，参与广泛的细胞过程。该分子在致癌作用中具有矛盾的作用，因为它既可以抑制又可以促进肿瘤生长。本项目旨在探讨 Sirt6 在弥漫性大 B 细胞淋巴瘤（DLBCL）中的表达和功能，特别是新型小分子 Sirt6 靶向抑制剂 OSS_128167 的调节作用。
方法
通过免疫组织化学（IHC）评估 Sirt6 在石蜡包埋组织中的表达。从基因表达综合数据库中获得微阵列数据集 GSE32918 和 GSE83632，并进行生存分析。将编码 shSirt6、lvSirt6 或空载体慢病毒载体稳定转染至 DLBCL 细胞中。用 shSirt6 转染的 LY1 细胞进行 RNA 测序（RNA-seq）分析，对基因本体论（GO）和基因集富集分析（GSEA）的功能富集分析。将 DLBCL 细胞皮下注射到 SCID beige 小鼠中建立异种移植模型。
结果
发现 Sirt6 在 DLBCL 中过度表达，与预后不良相关。Sirt6 缺失的 DLBCL 细胞对化疗更敏感，凋亡率更高，细胞增殖功能障碍，细胞周期在 G2 和 M 期之间停滞。选择性 OSS_128167 介导的 Sirt6 阻断与 Sirt6 敲低的 DLBCL 细胞相比具有相似的抗淋巴瘤作用。Sirt6 下调后，PI3K 信号及其下游靶标的磷酸化减少。接受 OSS_128167 治疗或 Sirt6 敲低的异种移植模型显示肿瘤生长受到抑制，Ki-67 水平降低。
结论
这些发现首次提供了 Sirt6 在 DLBCL 中致癌活性的机制见解，并强调了 OSS_128167 在 DLBCL 新型治疗策略中的潜力。
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