Ioris Rafael M, Galié Mirco, Ramadori Giorgio, Anderson Jason G, Charollais Anne, Konstantinidou Georgia, Brenachot Xavier, Aras Ebru, Goga Algera, Ceglia Nicholas, Sebastián Carlos, Martinvalet Denis, Mostoslavsky Raul, Baldi Pierre, Coppari Roberto
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Diabetes Center of the Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland.
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Switzerland; Department of Neurosciences, Biomedicine and Movement, University of Verona, Verona 37134, Italy.
Cell Rep. 2017 Feb 21;18(8):1858-1868. doi: 10.1016/j.celrep.2017.01.065.
Cancer stem cells (CSCs) have high tumorigenic capacity. Here, we show that stem-like traits of specific human cancer cells are reduced by overexpression of the histone deacetylase sirtuin 6 (SIRT6). SIRT6-sensitive cancer cells bear mutations that activate phosphatidylinositol-3-kinase (PI3K) signaling, and overexpression of SIRT6 reduces growth, progression, and grade of breast cancer in a mouse model with PI3K activation. Tumor metabolomic and transcriptomic analyses reveal that SIRT6 overexpression dampens PI3K signaling and stem-like characteristics and causes metabolic rearrangements in this cancer model. Ablation of a PI3K activating mutation in otherwise isogenic cancer cells is sufficient to convert SIRT6-sensitive into SIRT6-insensitive cells. SIRT6 overexpression suppresses PI3K signaling at the transcriptional level and antagonizes tumor sphere formation independent of its histone deacetylase activity. Our data identify SIRT6 as a putative molecular target that hinders stemness of tumors with PI3K activation.
癌症干细胞（CSCs）具有很高的致瘤能力。在此，我们表明，组蛋白去乙酰化酶沉默调节蛋白6（SIRT6）的过表达可降低特定人类癌细胞的干细胞样特性。对SIRT6敏感的癌细胞携带激活磷脂酰肌醇-3-激酶（PI3K）信号传导的突变，在PI3K激活的小鼠模型中，SIRT6的过表达可降低乳腺癌的生长、进展和分级。肿瘤代谢组学和转录组学分析表明，SIRT6的过表达可抑制PI3K信号传导和干细胞样特征，并在该癌症模型中引起代谢重排。在其他方面同基因的癌细胞中消除PI3K激活突变足以将对SIRT6敏感的细胞转变为对SIRT6不敏感的细胞。SIRT6的过表达在转录水平上抑制PI3K信号传导，并拮抗肿瘤球形成，且与其组蛋白去乙酰化酶活性无关。我们的数据确定SIRT6是一个假定的分子靶点，可阻碍PI3K激活的肿瘤的干性。
