Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
Lab Invest. 2015 Dec;95(12):1363-73. doi: 10.1038/labinvest.2015.119. Epub 2015 Sep 14.
Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (P<0.05), and its overexpression was associated with a shorter survival (P<0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.
Sirtuin 1（SIRT1）最初被鉴定为长寿基因，可被热量限制诱导，通过去乙酰化组蛋白和 p53 等靶蛋白来调节各种细胞功能，包括 DNA 修复、细胞存活和代谢。这些功能被认为具有双重作用，既能预防也能促进癌症的发生。本研究旨在阐明 SIRT1 在子宫内膜癌中的表达和作用。由于高热量饮食是子宫内膜癌的一个众所周知的危险因素，我们首先假设 SIRT1 可能在肥胖女性的正常子宫内膜腺细胞中下调。然而，SIRT1 的表达与体重指数（BMI）之间没有相关性。相比之下，无论 BMI 如何，SIRT1 的免疫组化表达在子宫内膜癌（108 例）中均显著高于正常子宫内膜（60 例）（P<0.05），其过表达与较短的生存期相关（P<0.05）。我们在体内的实验表明，SIRT1 加速了子宫内膜癌细胞系（HHUA、HEC151 和 HEC1B）的增殖。SIRT1 过表达显著增强了 HHUA 细胞对顺铂和紫杉醇的耐药性。尽管 p53 是 SIRT1 的重要靶蛋白，但选择性 SIRT1 抑制剂（EX527）在三种子宫内膜癌细胞系中，无论 p53 突变状态如何，均能显著抑制细胞增殖和对顺铂的耐药性。此外，HHUA 细胞中 SIRT1 的过表达加速了裸鼠肿瘤的生长和对顺铂的耐药性，而 EX527 显著抑制了 HHUA 和 HEC1B 细胞肿瘤的生长。在这些小鼠中未观察到 EX527 的不良反应。总之，SIRT1 参与了与子宫内膜癌相关的侵袭性行为的获得，SIRT1 抑制剂 EX527 可能是治疗这种恶性肿瘤的有用药物。
