组蛋白去乙酰化酶 SIRT6 是一种肿瘤抑制因子，可控制癌症代谢。

The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism.

机构信息

The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.

出版信息

Cell. 2012 Dec 7;151(6):1185-99. doi: 10.1016/j.cell.2012.10.047.

DOI:10.1016/j.cell.2012.10.047

PMID:23217706

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3526953/

Abstract

Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.

摘要

细胞代谢的重编程是肿瘤发生过程中的一个关键事件。尽管几十年来人们一直都知道（瓦伯格效应），但调节这种转变的分子机制仍未被探索。在这里，我们发现 SIRT6 是一种肿瘤抑制因子，可调节癌细胞中的有氧糖酵解。重要的是，SIRT6 的缺失会导致肿瘤形成，而不会激活已知的致癌基因，而转化的 SIRT6 缺陷细胞显示出增强的糖酵解和肿瘤生长，表明 SIRT6 在癌症的建立和维持中都发挥作用。通过使用条件性 SIRT6 等位基因，我们表明 SIRT6 在体内的缺失会增加肿瘤的数量、大小和侵袭性。SIRT6 还通过核心抑制 MYC 转录活性来作为核糖体代谢的调节剂。最后，Sirt6 在几种人类癌症中选择性地下调，并且 SIRT6 的表达水平可预测预后和无肿瘤生存率，突出了 SIRT6 作为癌症代谢的关键调节剂的作用。我们的研究揭示了 SIRT6 作为一种有效的肿瘤抑制因子，可抑制癌症代谢。