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Updated: Mar 16, 2026

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity

Upal Basu-Roy1, Eugenia Han2, Kirk Rattanakorn1

  • 1Department of Microbiology, NYU School of Medicine, New York, NY, USA.

Oncotarget
|August 17, 2016
PubMed

Insights

Thiazolidinedione (TZD) drugs, used for diabetes, can halt osteosarcoma (OS) growth and promote fat cell differentiation by activating PPARγ. This repurposed therapy targets cancer stem cells, offering a new treatment avenue for this aggressive pediatric bone cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osteosarcoma (OS) is an aggressive pediatric bone cancer with immature tumor cells that resist differentiation into bone-forming osteoblasts.
  • OS cells possess mesenchymal stem cell-like properties, responding to adipogenic stimuli.

Purpose of the Study:

  • To investigate the potential of PPARγ agonists, specifically thiazolidinedione (TZD) drugs, in inducing differentiation and growth arrest in osteosarcoma.
  • To elucidate the molecular mechanisms underlying TZD action in OS cells and tumors.

Main Methods:

  • Treatment of human, mouse, and canine OS cells and in vivo mouse models with TZD drugs.
  • Gene expression analysis to identify affected pathways (lipid metabolism, Hippo-YAP, Wnt signaling).
  • Assessment of transcription factor localization (SOX2, YAP) and PPARγ dependency.

Main Results:

  • TZDs induced growth arrest and adipogenic differentiation in OS cells and tumors.
  • Gene expression changes indicated TZD-mediated suppression of Hippo-YAP and Wnt signaling pathways.
  • TZD efficacy was linked to high SOX2 expression and PPARγ dependency, affecting SOX2 and YAP localization.
  • A TZD-regulated gene signature predicted patient outcomes.

Conclusions:

  • PPARγ agonists (TZDs) can induce osteosarcoma cell differentiation and inhibit tumor growth, mimicking tumor-suppressive pathways like the Hippo pathway.
  • Drug repurposing of TZDs presents a promising differentiation therapy strategy for osteosarcoma, particularly targeting cancer stem cells.
Keywords:
adipocytecancer stem cellsosteoblast lineageosteosarcomathiazolidinediones

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