First Department of Internal Medicine , University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
Hepatology. 2013 Sep;58(3):1054-64. doi: 10.1002/hep.26413. Epub 2013 Jul 30.
Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD+-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. The role of SIRT6 in development and progression of hepatocellular carcinoma is currently unknown. We first investigated SIRT6 expression in 153 primary human liver cancers and in normal and cirrhotic livers using microarray analysis. SIRT6 was significantly down-regulated in both cirrhotic livers and cancer. A Sirt6 knockout (KO) gene expression signature was generated from primary hepatoctyes isolated from 3-week-old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed up-regulation of established hepatocellular carcinoma (HCC) biomarkers alpha-fetoprotein (Afp), insulin-like growth factor 2 (Igf2), H19, and glypican-3. Furthermore, decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis-insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes, such as global hypomethylation, as well as metabolic changes, such as hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had a prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we demonstrated that the Sirt6-KO signature possessed a predictive value for tumors other than HCC (e.g., breast and lung cancer).
Loss of SIRT6 induces epigenetic changes that may be relevant to chronic liver disease and HCC development. Down-regulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype that ultimately has relevance for outcome of HCC and other cancer patients.
Sirtuin 6（SIRT6）是 NAD+-依赖性脱乙酰酶家族的成员。在小鼠中基因敲除 SIRT6 会导致严重的退行性表型，肝功能受损和早逝。SIRT6 在肝细胞癌的发生和发展中的作用目前尚不清楚。我们首先使用微阵列分析研究了 153 例原发性人肝癌以及正常和肝硬化肝脏中的 SIRT6 表达。在肝硬化和癌症中，SIRT6 的表达均显著下调。从 3 周龄 Sirt6 缺陷动物分离的原代肝细胞中生成了 Sirt6 敲除（KO）基因表达特征。Sirt6 缺陷的肝细胞显示出已建立的肝细胞癌（HCC）生物标志物α-胎蛋白（Afp），胰岛素样生长因子 2（Igf2），H19 和糖蛋白 3 的上调。此外，在已知对细胞凋亡不敏感的肝癌细胞系中观察到 SIRT6 表达降低。在 HepG2 细胞中重新表达 SIRT6 可增加对 CD95 刺激或化学疗法治疗的细胞凋亡敏感性。Sirt6 的缺失表现为致癌变化，例如整体低甲基化，以及代谢变化，例如低血糖和脂肪沉积增加。肝细胞特异性 Sirt6-KO 特征具有预后影响，并在 AFP 水平高且复发疾病的分化不良肿瘤患者中富集。最后，我们证明了 Sirt6-KO 特征对除 HCC 以外的肿瘤（例如乳腺癌和肺癌）具有预测价值。
SIRT6 的缺失诱导了可能与慢性肝病和 HCC 发展相关的表观遗传变化。SIRT6 的下调以及由 SIRT6 缺失引起的基因失调在肝癌发生中具有致癌作用。我们的数据表明，一种表观遗传调节剂的缺乏使肿瘤发生表型易发生，最终对 HCC 和其他癌症患者的预后具有重要意义。
