Regulation of Serine-Threonine Kinase Akt Activation by NAD+-Dependent Deacetylase SIRT7.
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.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Jia
J
Yu
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Bo
B
Qin
Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Fengying
F
Wu
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Sisi
S
Qin
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic School of Medicine and the Mayo Clinic Medical Scientist Training Program, Rochester, MN 55905, USA.
Somaira
S
Nowsheen
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Shan
S
Shan
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic School of Medicine and the Mayo Clinic Medical Scientist Training Program, Rochester, MN 55905, USA.
Jacqueline
J
Zayas
Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Huadong
H
Pei
Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: lou.zhenkun@mayo.edu.
Zhenkun
Z
Lou
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: wang.liewei@mayo.edu.
Liewei
L
Wang
D000107:Acetylation; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D009243:NAD / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
D008239:Lysine; D009243:NAD; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D037761:Sirtuins; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C510661:SIRT7 protein, human
Akt signaling pathway; SIRT7; breast cancer; chemo-sensitivity