文章：

sirtuins在癌症中的多重功能

The multifaceted functions of sirtuins in cancer

原文发布日期：2015-09-18

DOI: 10.1038/nrc3985

类型: Review Article

开放获取: 否

要点：

1. Sirtuins are NAD⁺-dependent enzymes that modulate the activities of target proteins, mediate changes in the metabolic status of cells and regulate diseases of ageing, including neurodegeneration, diabetes, cardiovascular diseases and cancer.
2. Sirtuin 1 (SIRT1) was the first sirtuin to be shown to be involved in cancer. It was demonstrated that SIRT1 represses p53-mediated tumour suppression. Since this finding, SIRT1 has been shown to have both tumour-suppressive and oncogenic roles, depending on the type and stage of cancer.
3. The mitochondrial sirtuin SIRT3 regulates levels of reactive oxygen species (ROS). Loss of SIRT3 results in increased levels of ROS, with subsequent activation of hypoxia-inducible factor 1α (HIF1α) and increased expression of HIF1 target genes, including glycolysis and angiogenesis genes, which favour tumour growth.
4. The mitochondrial sirtuin SIRT4 regulates glutamine metabolism by inhibiting glutamate dehydrogenase (GDH), the rate-limiting enzyme in glutaminolysis. Loss of SIRT4 leads to increased glutamine catabolism, a pathway that promotes tumour growth.
5. The chromatin-bound sirtuin SIRT6 regulates cancer metabolism and inflammation by acting as a co-repressor for HIF1α, MYC and nuclear factor-κB (NF-κB). Loss of SIRT6 results in increased expression of glycolysis, glutaminolysis and ribosomal genes, all of which favour proliferation and tumorigenesis.
6. SIRT1 and SIRT6 promote genomic stability by regulating both single- and double-strand DNA break-repair pathways.

要点翻译：

1. Sirtuins是一类依赖NAD+的酶，它们通过调控靶蛋白活性、介导细胞代谢状态变化，从而影响衰老相关疾病进程，包括神经退行性疾病、糖尿病、心血管疾病和癌症。
2. Sirtuin 1（SIRT1）是首个被发现与癌症相关的sirtuin。研究表明SIRT1能够抑制p53介导的肿瘤抑制功能。随着研究深入，发现SIRT1在癌症中兼具抑癌与促癌双重作用，其具体功能取决于癌症类型及发展阶段。
3. 线粒体sirtuin SIRT3通过调节活性氧（ROS）水平发挥作用。SIRT3缺失会导致ROS水平升高，进而激活缺氧诱导因子1α（HIF1α），促进HIF1靶基因（包括糖酵解和血管生成相关基因）的表达，从而推动肿瘤生长。
4. 线粒体sirtuin SIRT4通过抑制谷氨酰胺分解过程中的限速酶——谷氨酸脱氢酶（GDH）来调控谷氨酰胺代谢。SIRT4缺失会增强谷氨酰胺分解代谢，这一代谢途径能够促进肿瘤生长。
5. 染色质结合型sirtuin SIRT6通过作为HIF1α、MYC和核因子κB（NF-κB）的共抑制因子，调控癌症代谢和炎症反应。SIRT6缺失会导致糖酵解、谷氨酰胺分解及核糖体基因表达上调，这些变化均有利于细胞增殖和肿瘤发生。
6. SIRT1和SIRT6通过同时调控单链和双链DNA断裂修复途径，共同维护基因组稳定性。

英文摘要：

The sirtuins (SIRTs; of which there are seven in mammals) are NAD+-dependent enzymes that regulate a large number of cellular pathways and forestall the progression of ageing and age-associated diseases. In recent years, the role of sirtuins in cancer biology has become increasingly apparent, and growing evidence demonstrates that sirtuins regulate many processes that go awry in cancer cells, such as cellular metabolism, the regulation of chromatin structure and the maintenance of genomic stability. In this article, we review recent advances in our understanding of how sirtuins affect cancer metabolism, DNA repair and the tumour microenvironment and how activating or inhibiting sirtuins may be important in preventing or treating cancer.

摘要翻译： 

Sirtuins（SIRTs；哺乳动物中有七种）是依赖NAD+的酶，可调节大量细胞通路，并延缓衰老及与年龄相关疾病的进展。近年来，sirtuins在癌症生物学中的作用日益明显，越来越多的证据表明，sirtuins调控许多在癌细胞中出现异常的过程，如细胞代谢、染色质结构调节和基因组稳定性维持。本文综述了我们近期对sirtuins如何影响癌症代谢、DNA修复及肿瘤微环境的理解，并探讨激活或抑制sirtuins在癌症预防或治疗中的潜在重要性。

原文链接：

The multifaceted functions of sirtuins in cancer