Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

J Clin Invest. 2017 Jun 1;127(6):2159-2175. doi: 10.1172/JCI90077. Epub 2017 Apr 24.

Abstract

Geminin expression is essential for embryonic development and the maintenance of chromosomal integrity. In spite of this protective role, geminin is also frequently overexpressed in human cancers and the molecular mechanisms underlying its role in tumor progression remain unclear. The histone deacetylase HDAC3 modulates transcription factors to activate or suppress transcription. Little is known about how HDAC3 specifies substrates for modulation among highly homologous transcription factor family members. Here, we have demonstrated that geminin selectively couples the transcription factor forkhead box O3 (FoxO3) to HDAC3, thereby specifically facilitating FoxO3 deacetylation. We determined that geminin-associated HDAC3 deacetylates FoxO3 to block its transcriptional activity, leading to downregulation of the downstream FoxO3 target Dicer, an RNase that suppresses metastasis. Breast cancer cells depleted of geminin or HDAC3 exhibited poor metastatic potential that was attributed to reduced suppression of the FoxO3-Dicer axis. Moreover, elevated levels of geminin, HDAC3, or both together with decreased FoxO3 acetylation and reduced Dicer expression were detected in aggressive human breast cancer specimens. These results underscore a prominent role for geminin in promoting breast cancer metastasis via the enzyme-substrate-coupling mechanism in HDAC3-FoxO3 complex formation.

MeSH terms

  • Acetylation
  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / secondary
  • Carcinoma, Intraductal, Noninfiltrating / metabolism
  • Carcinoma, Intraductal, Noninfiltrating / secondary
  • Cell Movement
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Female
  • Forkhead Box Protein O3 / metabolism*
  • Geminin / physiology*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HEK293 Cells
  • Histone Deacetylases / metabolism
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / secondary
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / biosynthesis
  • Neoplasm Transplantation
  • Protein Processing, Post-Translational*
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism

Substances

  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • GMNN protein, human
  • Geminin
  • MicroRNAs
  • DICER1 protein, human
  • Ribonuclease III
  • Histone Deacetylases
  • histone deacetylase 3
  • DEAD-box RNA Helicases