CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance

Mol Cancer Ther. 2015 Sep;14(9):2090-102. doi: 10.1158/1535-7163.MCT-15-0017. Epub 2015 Jul 3.


Tumor adaptive resistance to therapeutic radiation remains a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD(+)-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors, including colon cancer HCT-116, glioblastoma U87, and breast cancer MDA-MB231 cells. SIRT3 transcriptional activation is due to SIRT3 promoter activation controlled by the stress transcription factor NF-κB. Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. Cells expressing Thr150Ala/Ser159Ala-mutant SIRT3 show a reduction in mitochondrial protein lysine deacetylation, Δψm, MnSOD activity, and mitochondrial ATP generation. The clonogenicity of Thr150Ala/Ser159Ala-mutant transfectants is lower and significantly decreased under radiation. Tumors harboring Thr150Ala/Ser159Ala-mutant SIRT3 show inhibited growth and increased sensitivity to in vivo local irradiation. These results demonstrate that enhanced SIRT3 transcription and posttranslational modifications in mitochondria contribute to adaptive radioresistance in tumor cells. CDK1-mediated SIRT3 phosphorylation is a potential effective target to sensitize tumor cells to radiotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • CDC2 Protein Kinase
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / metabolism*
  • Disease Models, Animal
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Mitochondria / metabolism*
  • Mitochondria / radiation effects
  • Mitochondrial Proteins / metabolism
  • Mutation
  • NF-kappa B / metabolism
  • Neoplasms / genetics*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms / radiotherapy
  • Phosphorylation
  • Radiation Tolerance / genetics*
  • Sirtuin 3 / genetics*
  • Sirtuin 3 / metabolism
  • Transcription, Genetic
  • Transcriptional Activation*


  • Mitochondrial Proteins
  • NF-kappa B
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • Sirtuin 3