Yu Jia, Qin Bo, Wu Fengying, Qin Sisi, Nowsheen Somaira, Shan Shan, Zayas Jacqueline, Pei Huadong, Lou Zhenkun, Wang Liewei
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Cell Rep. 2017 Jan 31;18(5):1229-1240. doi: 10.1016/j.celrep.2017.01.009.
The Akt pathway is a central regulator that promotes cell survival in response to extracellular signals. Depletion of SIRT7, an NAD-dependent deacetylase that is the least-studied sirtuin, is known to significantly increase Akt activity in mice through unknown mechanisms. In this study, we demonstrate that SIRT7 depletion in breast cancer cells results in Akt hyper-phosphorylation and increases cell survival following genotoxic stress. Mechanistically, SIRT7 specifically interacts with and deacetylates FKBP51 at residue lysines 28 and 155 (K28 and K155), resulting in enhanced interactions among FKBP51, Akt, and PHLPP, as well as Akt dephosphorylation. Mutating both lysines to arginines abolishes the effect of SIRT7 on Akt activity through FKBP51 deacetylation. Finally, energy stress strengthens SIRT7-mediated effects on Akt dephosphorylation through FKBP51 and thus sensitizes cancer cells to cytotoxic agents. These results reveal a direct role of SIRT7 in Akt regulation and raise the possibility of using the glucose analog 2-deoxy-D-glucose (2DG) as a chemo-sensitizing agent.
Akt信号通路是一种核心调节因子，可响应细胞外信号促进细胞存活。SIRT7是一种依赖NAD的去乙酰化酶，也是研究最少的沉默调节蛋白，已知其缺失会通过未知机制显著增加小鼠体内的Akt活性。在本研究中，我们证明乳腺癌细胞中SIRT7的缺失会导致Akt过度磷酸化，并增加基因毒性应激后的细胞存活率。从机制上讲，SIRT7特异性地与FKBP51在赖氨酸28和155位点（K28和K155）相互作用并使其去乙酰化，导致FKBP51、Akt和PHLPP之间的相互作用增强，以及Akt去磷酸化。将这两个赖氨酸突变为精氨酸会消除SIRT7通过FKBP51去乙酰化对Akt活性的影响。最后，能量应激通过FKBP51增强SIRT7介导的对Akt去磷酸化的作用，从而使癌细胞对细胞毒性药物敏感。这些结果揭示了SIRT7在Akt调节中的直接作用，并提出了使用葡萄糖类似物2-脱氧-D-葡萄糖（2DG）作为化学增敏剂的可能性。
