A systems biology approach to identify molecular pathways altered by HDAC inhibition in osteosarcoma

Luke Anthony Wittenburg, Andrey A. Ptitsyn, Douglas H. Thamm

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Osteosarcoma (OS) is the most common primary tumor in humans and dogs affecting the skeleton, and spontaneously occurring OS in dogs serves as an extremely useful model. Unacceptable toxicities using current treatment protocols prevent further dose-intensification from being a viable option to improve patient survival and thus, novel treatment strategies must be developed. Histone deacetylase inhibitors (HDACi) have recently emerged as a promising class of therapeutics demonstrating an ability to enhance the anti-tumor activity of traditional chemotherapeutics. To date, gene expression analysis of OS cell lines treated with HDACi has not been reported, and evaluation of the resultant gene expression changes may provide insight into the mechanisms that lead to success of HDACi. Canine OS cells, treated with a clinically relevant concentration of the HDACi valproic acid (VPA), were used for expression analysis on the Affymetrix canine v2.0 genechip. Differentially expressed genes were grouped into pathways based upon functional annotation; pathway analysis was performed with MetaCore and Ingenuity Pathways Analysis software. Validation of microarray results was performed by a combination of qRT-PCR and functional/biochemical assays revealing oxidative phosphorylation, cytoskeleton remodeling, cell cycle, and biquitin-proteasome among those pathways most affected by HDACi. The mitomycin C-bioactivating enzyme NQ01 also demonstrated upregulation following VPA treatment, leading to synergistic reductions in cell viability. These results provide a better understanding of the mechanisms by which HDACi exert their effect in OS, and have the potential to identify biomarkers that may serve as novel targets and/or predictors of response to HDACicontaining combination therapies in OS.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalJournal of Cellular Biochemistry
Volume113
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

Fingerprint

Histone Deacetylase Inhibitors
Systems Biology
Osteosarcoma
Cells
Valproic Acid
Gene expression
Canidae
Tumors
Dogs
Gene Expression
Oxidative Phosphorylation
Mitomycin
Biomarkers
Proteasome Endopeptidase Complex
Therapeutics
Microarrays
Clinical Protocols
Cytoskeleton
Skeleton
Toxicity

Keywords

  • Expression profiling
  • Osteosarcoma
  • Pathway analysis
  • Valproate

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

A systems biology approach to identify molecular pathways altered by HDAC inhibition in osteosarcoma. / Wittenburg, Luke Anthony; Ptitsyn, Andrey A.; Thamm, Douglas H.

In: Journal of Cellular Biochemistry, Vol. 113, No. 3, 03.2012, p. 773-783.

Research output: Contribution to journalArticle

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