PDF(Pubmed)
Abstract：
Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomal-dependent degradation of ARF. We show that SIRT7-mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression.
摘要：
Sirtuin7（SIRT7）是哺乳动物烟酰胺腺嘌呤二核苷酸（NAD）依赖性组蛋白/蛋白质脱乙酰酶家族的成员，被称为sirtuins。它在许多恶性肿瘤中充当有效的癌基因，但SIRT7用于维持肺癌进展的分子机制在很大程度上仍未表征.我们证明SIRT7通过使肿瘤抑制因子替代阅读框（ARF）不稳定而在肺癌细胞中发挥致癌功能。SIRT7直接与ARF相互作用，阻止ARF与核蛋白结合，从而促进ARF的蛋白酶体依赖性降解。我们表明SIRT7介导的ARF降解增加了原瘤基因的表达，并在小鼠异种移植模型中刺激了非小细胞肺癌（NSCLC）细胞的体外和体内增殖。人类肺腺癌转录组数据的生物信息学分析显示，SIRT7表达与通常被ARF抑制的基因活性增加之间存在相关性。我们认为SIRT7-ARF信号的破坏可以稳定ARF，从而减弱癌细胞的增殖。提供缓解NSCLC进展的策略。
