Regulation of Serine-Threonine Kinase Akt Activation by NAD+-Dependent Deacetylase SIRT7

Jia Yu, Bo Qin, Fengying Wu, Sisi Qin, Somaira Nowsheen, Shan Shan, Jacqueline Zayas, Huadong Pei, Zhenkun Lou, Liewei Wang

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1229-1240
Number of pages12
JournalCell reports
Volume18
Issue number5
DOIs
StatePublished - Jan 31 2017

Keywords

  • Akt signaling pathway
  • SIRT7
  • breast cancer
  • chemo-sensitivity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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