SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein-Dependent Apoptotic Pathway
SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein-Dependent Apoptotic Pathway
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SIRT6 过表达通过 BCL2 相关 X 蛋白依赖性细胞凋亡途径增强肝细胞癌中的细胞凋亡逃避。
DOI：
10.1158/1078-0432.ccr-15-1638
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发表时间：
2016-07-01
影响因子：
11.5
通讯作者：
Chen, Juan
中科院分区：
文献类型：
--
作者：
Ran, Long-Kuan;Chen, Yong;Chen, Juan
目的：表征SIRT6在肝细胞癌（HCC）中的功能作用。实验设计：通过免疫组织化学检查60对石蜡包埋的HCC组织和邻近非肿瘤肝组织中SIRT6的表达。通过蛋白质印迹分析和 qPCR 分析 101 对冷冻 HCC 组织和邻近非肿瘤肝组织中 SIRT6 的表达。在体外和体内研究了HCC细胞系中SIRT6过表达和敲低的生物学后果。结果：SIRT6表达在临床HCC样本中频繁上调，其表达与肿瘤分级（P = 0.02）、肿瘤大小（P = 0.02）、血管侵犯（P = 0.004）和较短生存期（P = 0.024）高度相关。在体外，多种肝癌细胞系中 SIRT6 的缺失抑制了它们的生长并诱导细胞凋亡。在分子水平上，我们观察到 BCL2 相关 X 蛋白 (Bax) 信号通路（决定癌细胞凋亡的主要通路）的激活受到 SIRT6 通过其脱乙酰酶活性的调节。 SIRT6 被招募到 Bax 的启动子上，在那里它使组蛋白 3 赖氨酸 9 去乙酰化并抑制其启动子活性。在 SIRT6 缺失的细胞中，转录因子（p53 和 E2F-1）与 Bax 启动子的结合也普遍增加。在小鼠异种移植物中，SIRT6 抑制可抑制肿瘤生长并诱导细胞凋亡。最后，人HCC样本中SIRT6和Bax mRNA表达量呈负相关。结论：SIRT6是肝癌发生过程中重要的促癌因子。因此，SIRT6的治疗靶向可能为HCC治疗提供选择。 (C) 2016 年 AACR。
Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo.Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment. (C) 2016 AACR.